Derivatives of 4-(2-amino-1-hydroxyethyl)phenol as agonists of the β2 adrenergic receptor

ABSTRACT

The present disclosure relates to 4-(2-amino-1-hydroxyethyl)phenol derivatives of formula (I) as well as pharmaceutical compositions comprising them, and their use in therapy as agonists of the BETA2 adrenergic receptor.

This application is a divisional of application Ser. No. 11/920,561,which has a §371 date of Feb. 11, 2008 now U.S. Pat. No. 7,964,615, andwhich is the U.S. national stage application of InternationalApplication No. PCT/EP2006/004680 filed on May 17, 2006, which claimsthe benefit of priority from Spanish Patent Application No. P200501229,filed on May 20, 2005. Both of these applications are hereinincorporated by reference.

FIELD OF THE INVENTION

The present invention is directed to novel β2 adrenergic receptoragonists. The invention is also directed to pharmaceutical compositionscomprising such compounds, methods of using such compounds to treatdiseases associated with β2 adrenergic receptor activity, and processesand intermediates useful for preparing such compounds.

BACKGROUND OF THE INVENTION

β2 adrenergic receptor agonists are recognized as effective drugs forthe treatment of pulmonary diseases such as asthma and chronicobstructive pulmonary disease (including chronic bronchitis andemphysema). β2 adrenergic receptor agonists are also useful for treatingpre-term labor, glaucoma and are potentially useful for treatingneurological disorders and cardiac disorders.

In spite of the success that has been achieved with certain β2adrenergic receptor agonists, current agents possess less than desirablepotency, selectivity, onset, and/or duration of action. Thus, there is aneed for additional β2 adrenergic receptor agonists having improvedproperties. Preferred agents may possess, among other properties,improved potency, selectivity, onset, improved safety margins, improvedtherapeutic window and/or duration of action.

BRIEF DESCRIPTION OF THE DRAWING

FIG. 1 shows compounds of formula (I) in accordance with embodimentsdescribed in this application.

SUMMARY OF THE INVENTION

The invention provides novel compounds that possess β2 adrenergicreceptor agonist activity. Accordingly, there is provided a compound ofthe invention which is a compound of formula (I):

wherein:

R¹ is a group selected from —CH₂OH, —NHC(O)H and

-   -   R² is a hydrogen atom; or    -   R¹ together with R² form the group —NH—C(O)—CH═CH— wherein the        nitrogen atom is bound to the carbon atom in the phenyl ring        holding R¹ and the carbon atom is bound to the carbon atom in        the phenyl ring holding R²    -   R³ is selected from hydrogen and halogen atoms or groups        selected from —SO—R⁵, —SO₂—R⁵, —NH—CO—NH₂, —CONH₂, hydantoino,        C₁₋₄alkyl, C₁₋₄alkoxy and —SO₂NR⁵R⁶    -   R⁴ is selected from hydrogen atoms, halogen atoms and C₁₋₄alkyl        groups    -   R⁵ is a C₁₋₄alkyl group or C₃₋₈cycloalkyl group    -   R⁶ is independently selected from hydrogen atoms and C₁₋₄alkyl        groups    -   n, p and q are independently 0, 1, 2, 3 or 4    -   m and s are independently 0, 1, 2 or 3    -   r is 0, 1 or 2        -   with the provisos that:        -   at least one of m and r is not 0        -   the sum n+m+p+q+r+s is 7, 8, 9, 10, 11, 12 or 13        -   the sum q+r+s is 2, 3, 4, 5 or 6            or a pharmaceutically-acceptable salt or solvate or            stereoisomer thereof.

The invention also provides a pharmaceutical composition comprising acompound of the invention and a pharmaceutically-acceptable carrier. Theinvention further provides combinations comprising a compound of theinvention and one or more other therapeutic agents and pharmaceuticalcompositions comprising such combinations.

The invention also provides a method of treating a disease or conditionassociated with β2 adrenergic receptor activity (e.g. a pulmonarydisease, such as asthma or chronic obstructive pulmonary disease,pre-term labor, glaucoma, a neurological disorder, a cardiac disorder,or inflammation) in a mammal, comprising administering to the mammal, atherapeutically effective amount of a compound of the invention. Theinvention further provides a method of treatment comprisingadministering a therapeutically effective amount of a combination of acompound of the invention together with one or more other therapeuticagents.

In separate and distinct aspects, the invention also provides syntheticprocesses and intermediates described herein, which are useful forpreparing compounds of the invention.

The invention also provides a compound of the invention as describedherein for use in medical therapy, as well as the use of a compound ofthe invention in the manufacture of a formulation or medicament fortreating a disease or condition associated with β2 adrenergic receptoractivity (e.g. a pulmonary disease, such as asthma or chronicobstructive pulmonary disease, pre-term labor, glaucoma, a neurologicaldisorder, a cardiac disorder, or inflammation) in a mammal.

DETAILED DESCRIPTION OF THE INVENTION

When describing the compounds, compositions and methods of theinvention, the following terms have the following meanings, unlessotherwise indicated.

The term “therapeutically effective amount” refers to an amountsufficient to effect treatment when administered to a patient in need oftreatment.

The term “treatment” as used herein refers to the treatment of a diseaseor medical condition in a human patient which includes:

(a) preventing the disease or medical condition from occurring, i.e.,prophylactic treatment of a patient;

(b) ameliorating the disease or medical condition, i.e., causingregression of the disease or medical condition in a patient;

(c) suppressing the disease or medical condition, i.e., slowing thedevelopment of the disease or medical condition in a patient; or

(d) alleviating the symptoms of the disease or medical condition in apatient.

The phrase “disease or condition associated with β2 adrenergic receptoractivity” includes all disease states and/or conditions that areacknowledged now, or that are found in the future, to be associated withβ2 adrenergic receptor activity. Such disease states include, but arenot limited to, pulmonary diseases, such as asthma and chronicobstructive pulmonary disease (including chronic bronchitis andemphysema), as well as neurological disorders and cardiac disorders. β2adrenergic receptor activity is also known to be associated withpre-term labor (see International Patent Application Publication NumberWO 98/09632), glaucoma and some types of inflammation (see InternationalPatent Application Publication Number WO 99/30703 and Patent ApplicationPublication Number EP 1 078 629).

The term “pharmaceutically-acceptable salt” refers to a salt preparedfrom a base or acid which is acceptable for administration to a patient,such as a mammal. Such salts can be derived frompharmaceutically-acceptable inorganic or organic bases and frompharmaceutically-acceptable inorganic or organic acids.

Salts derived from pharmaceutically-acceptable acids include acetic,benzenesulfonic, benzoic, camphosulfonic, citric, ethanesulfonic,fumaric, gluconic, glutamic, hydrobromic, hydrochloric, lactic, maleic,malic, mandelic, methanesulfonic, mucic, nitric, pantothenic,phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic, xinafoic(1-hydroxy-2-naphthoic acid) and the like. Particularly preferred aresalts derived from fumaric, hydrobromic, hydrochloric, acetic, sulfuric,methanesulfonic, xinafoic, and tartaric acids.

Salts derived from pharmaceutically-acceptable inorganic bases includealuminum, ammonium, calcium, copper, ferric, ferrous, lithium,magnesium, manganic, manganous, potassium, sodium, zinc and the like.Particularly preferred are ammonium, calcium, magnesium, potassium andsodium salts.

Salts derived from pharmaceutically-acceptable organic bases includesalts of primary, secondary and tertiary amines, including substitutedamines, cyclic amines, naturally-occurring amines and the like, such asarginine, betaine, caffeine, choline, N,N′-dibenzylethylenediamine,diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol,ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine,glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine,methylglucamine, morpholine, piperazine, piperidine, polyamine resins,procaine, purines, theobromine, triethylamine, trimethylamine,tripropylamine, tromethamine and the like.

The term “solvate” refers to a complex or aggregate formed by one ormore molecules of a solute, i.e. a compound of the invention or apharmaceutically-acceptable salt thereof, and one or more molecules of asolvent. Such solvates are typically crystalline solids having asubstantially fixed molar ratio of solute and solvent. Representativesolvents include by way of example, water, methanol, ethanol,isopropanol, acetic acid, and the like. When the solvent is water, thesolvate formed is a hydrate.

It will be appreciated that the term “or a pharmaceutically-acceptablesalt or solvate of stereoisomer thereof” is intended to include allpermutations of salts, solvates and stereoisomers, such as a solvate ofa pharmaceutically-acceptable salt of a stereoisomer of a compound offormula (I).

The term “amino-protecting group” refers to a protecting group suitablefor preventing undesired reactions at an amino nitrogen. Representativeamino-protecting groups include, but are not limited to, formyl; acylgroups, for example alkanoyl groups, such as acetyl; alkoxycarbonylgroups, such as tert-butoxycarbonyl (Boc); arylmethoxycarbonyl groups,such as benzyloxycarbonyl (Cbz) and 9-fluorenylmethoxycarbonyl (Fmoc);arylmethyl groups, such as benzyl (Bn), trityl (Tr), and1,1-di-(4′-methoxyphenyl)methyl; silyl groups, such as trimethylsilyl(TMS) and tert-butyldimethylsilyl (TBS); and the like.

The term “hydroxy-protecting group” refers to a protecting groupsuitable for preventing undesired reactions at a hydroxy group.Representative hydroxy-protecting groups include, but are not limitedto, alkyl groups, such as methyl, ethyl, and tert-butyl; acyl groups,for example alkanoyl groups, such as acetyl; arylmethyl groups, such asbenzyl (Bn), p-methoxybenzyl (PMB), 9-fluorenylmethyl (Fm), anddiphenylmethyl (benzhydryl, DPM); silyl groups, such as trimethylsilyl(TMS) and tert-butyldimethylsilyl (TBS); and the like.

The compounds of the invention contain at least a chiral center.Accordingly, the invention includes racemic mixtures, enantiomers, andmixtures enriched in one or more stereoisomer. The scope of theinvention as described and claimed encompasses the racemic forms of thecompounds as well as the individual enantiomers, diastereomers, andstereoisomer-enriched mixtures.

In an embodiment the compounds of the present invention have at leastone of m and r with a value of 1.

In another embodiment the compounds of the present invention have thesum m+r with a value of 1.

In still another embodiment the compounds of the present invention havethe sum n+m+p+q+r+s with a value of 8, 9 or 10.

In still another embodiment the compounds of the present invention havethe sum q+r+s with a value of 2, 3 or 4.

In still another embodiment the compounds of he present invention have swith a value of 0 or 1.

In still another embodiment the compounds of the present invention havethe sum n+p with a value of 4, 5 or 6.

In still another embodiment the compounds of the present invention havethe sum q+s with a value of 1, 2, 3 or 4.

In still another embodiment the compounds of the present invention haveR³ selected from the group consisting of a hydrogen atom, an halogenatom or a methyl group.

In still another embodiment the compounds of the present invention haveR³ selected from the group consisting of chlorine or fluorine atom.

In still another embodiment the compounds of the present invention haveR³ being a methyl group.

In still another embodiment the compounds of the present invention haveR⁴ being a hydrogen atom.

In still another embodiment the compounds of the present invention haveR⁴ being a chlorine atom.

In still another embodiment the compounds of the present invention havem and s with a value of 0, r and q with a value of 1, the sum of n and pwith a value of 6 and R⁵ and R⁶ being both hydrogen atoms

Of particular interest are the compounds:

-   (R,S)-4-(2-{[6-(2,2-Difluoro-4-phenylbutoxy)hexyl]amino}-1-hydroxy-ethyl)-2-(hydroxymethyl)phenol-   (R,S)-4-(2-{[6-(2,2-Difluoro-2-phenylethoxy)hexyl]amino}-1-hydroxy-ethyl)-2-(hydroxymethyl)phenol-   (R,S)-4-(2-{[4,4-Difluoro-6-(4-phenylbutoxy)hexyl]amino}-1-hydroxy-ethyl)-2-(hydroxymethyl)phenol-   (R,S)-4-(2-{[6-(4,4-Difluoro-4-phenylbutoxy)hexyl]amino}-1-hydroxy-ethyl)-2-(hydroxymethyl)phenol-   (R,S)-5-(2-{[6-(2,2-Difluoro-2-phenylethoxy)hexyl]amino}-1-hydroxy-ethyl)-8-hydroxyquinolin-2(1H)-one-   (R,S)-4-[2-({6-[2,2-Difluoro-2-(3-methylphenyl)ethoxy]hexyl}amino)-1-hydroxyethyl]-2-(hydroxymethyl)phenol-   4-(1R)-2-{[6-(2,2-Difluoro-2-phenylethoxy)hexyl]amino}-1-hydroxyethyl)-2-(hydroxymethyl)phenol-   (R,S)-2-(Hydroxymethyl)-4-(1-hydroxy-2-{[4,4,5,5-tetrafluoro-6-(3-phenylpropoxy)hexyl]amino}ethyl)phenol-   (R,S)-[5-(2-{[6-(2,2-Difluoro-2-phenylethoxy)hexyl]amino}-1-hydroxy-ethyl)-2-hydroxyphenyl]formamide-   (R,S)-4-[2-({6-[2-(3-Bromophenyl)-2,2-difluoroethoxy]hexyl}amino)-1-hydroxyethyl]-2-(hydroxymethyl)phenol-   (R,S)-N-[3-(1,1-Difluoro-2-{[5-({2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}ethyl)phenyl]urea-   (R,S)-3-[3-(1,1-difluoro-2-{[6-({2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}ethyl)phenyl]imidazolidine-2,4-dione-   (R,S)-4-[2-({6-[2,2-difluoro-2-(3-methoxyphenyl)ethoxy]hexyl}amino)-1-hydroxyethyl]-2-(hydroxymethyl)phenol-   5-((1R)-2-{[6-(2,2-difluoro-2-phenylethoxy)hexyl]amino}-1-hydroxyethyl)-8-hydroxyquinolin-2(1H)-one-   4-((1R)-2-{[4,4-Difluoro-6-(4-phenylbutoxy)hexyl]amino}-1-hydroxy-ethyl)-2-(hydroxymethyl)phenol-   (R,S)-4-(2-{[6-(3,3-Difluoro-3-phenylpropoxy)hexyl]amino}-1-hydroxy    ethyl)-2-(hydroxymethyl)phenol-   (R)-4-(2-{[6-(2,2-Difluoro-2-phenylethoxy)-4,4-difluorohexyl]amino}-1-hydroxyethyl)-2-(hydroxymethyl)phenol-   (R,S)-4-(2-{[5-(2,2-difluoro-3-phenylpropoxy)hexyl]amino}-1-hydroxy    ethyl}-2-(hydroxymethyl)phenol, hydrochloride    and pharmaceutically-acceptable salts and solvates thereof.

The invention comprises also pharmaceutical compositions comprising atherapeutically effective amount of a compound as hereinabove definedand a pharmaceutically acceptable carrier.

In an embodiment of the present invention the pharmaceutical compositionfurther comprises a therapeutically effective amount of one or moreother therapeutic agents.

It is also an embodiment of the present invention that thepharmaceutical composition is formulated for administration byinhalation.

The compounds of the present invention as hereinabove defined may alsobe combined with one or more other therapeutic agents, in particular oneor more drugs selected from the group consisting of corticosteroids, anantichlolinergic agents and PDE4 inhibitors.

In a preferred embodiment of the present invention the combinationcomprises a compound of formula (I) as hereinabove defined and a drugselected from the group consisting of fluticasone propionate,6α,9α-difluoro-17α-[-(2-furanylcarbonyl)oxy]-11β-hydroxy-16α-methyl-3-oxo-androsta-1,4-diene-17β-carbothioicacid S-fluoromethyl ester, and6α,9α-difluoro-11β-hydroxy-16α-methyl-3-oxo-17.alpha.-propionyloxy-androsta-1,4-diene-17β-carbothioicacid S-(2-oxo-tetrahydro-furan-3S-yl) ester.

The invention is also directed to a method of treating a disease orcondition in a mammal associated with β2 adrenergic receptor activity,the method comprising administering to the mammal, a therapeuticallyeffective amount of a pharmaceutical composition comprising a β2adrenergic receptor agonist according to the present invention. It is ofparticular relevance the method applied to the treatment of a disease orcondition which is a pulmonary disease, preferably asthma or chronicobstructive pulmonary disease.

The method of treating a disease can also be applied within the scope ofthe present invention to the treatment of a disease or conditionselected from the group consisting of pre-term labor, glaucoma,neurological disorders, cardiac disorders, and inflammation.

General Synthetic Procedures

The compounds of the invention can be prepared using the methods andprocedures described herein, or using similar methods and procedures. Itwill be appreciated that where typical or preferred process conditions(i.e., reaction temperatures, times, mole ratios of reactants, solvents,pressures, etc.) are given, other process conditions can also be usedunless otherwise stated. Optimum reaction conditions may vary with theparticular reactants or solvent used, but such conditions can bedetermined by one skilled in the art by routine optimization procedures.

Additionally, as will be apparent to those skilled in the art,conventional protecting groups may be necessary to prevent certainfunctional groups from undergoing undesired reactions. The choice of asuitable protecting group for a particular functional group, as well assuitable conditions for protection and deprotection, are well known inthe art. For example, numerous protecting groups, and their introductionand removal, are described in T. W. Greene and G. M. Wuts, ProtectingGroups in Organic Synthesis, Third Edition, Wiley, New York, 1999, andreferences cited therein.

Processes for preparing compounds of the invention are provided asfurther embodiments of the invention and are illustrated by theprocedures below.

In general the compounds of formula (I) are obtained reacting a compoundof formula (II):

wherein R¹ and R² are as hereinabove defined, P¹ is a conventionalhydroxy protecting group such as benzyl group; with a compound offormula (III):

wherein n, m p, q, r and s are as hereinabove defined and G¹ is a groupselected from:

hydrogen or halogen atoms or groups selected from C₁₋₄ alkyl, C₁₋₄alkoxy, S—R⁵, SO—R⁵ and SO₂—R⁵ wherein R⁵ is a C₁₋₄ alkyl and C₃₋₆cycloalkyl and R⁴ is selected from hydrogen atom, halogen atoms and C₁₋₄alkyl groups.

The nature of the reacting groups G³ and G² depends on the couplingreaction that is employed to obtain the compounds of formula (I). Thedifferent coupling reactions between compound (II) (thephenylethanolamine moiety) and the corresponding compound (III) (thefluorinated moeity) are summarised in Scheme 1 and described below.

wherein R represents a group of formula:

In a first alternative phenylglyoxals of formula (IIa) (corresponding tocompounds of general formula (II) wherein G³ is a —CO—CHO group) canreact with a compound of formula (IIIf) (corresponding to compounds ofgeneral formula (III) wherein G² is a group —CH₂NH₂) to give, in areductive alkylation step, intermediates of formula (XI). This step canbe achieved in a variety of solvents, like tetrahydrofuran, alcohols asmethanol, ethanol or isopropyl alcohol, as well as a mixture of solventssuch as methanol/tetrahydrofuran or dimethylsulfoxide/methanol, thetemperature range being between 5° and 100° C.; more specificallybetween 15° and 70° C. The reducing agent may be a hydride like sodiumborohydride or sodium cyanoborohydride as well as hydrogen plus ahydrogenation catalyst like palladium on charcoal.

In a second alternative aminoalcohols of formula (IIe) (corresponding tocompounds of general formula (II) wherein G³ is a —CH(OH)—CH₂NH₂ group)can react with an aldehyde compound of formula (IIIc) (corresponding tocompounds of general formula (III) wherein G² is a group —CHO) to give,in an analogous reductive alkylation process the same intermediates offormula (XI). This step is carried out under similar conditions andsolvents as the previously described.

In a third alternative compounds of formula (IIe) (corresponding tocompounds of general formula (II) wherein G³ is a —CH(OH)—CH₂NH₂ group)are converted to the corresponding oxazolidinones derivatives of formula(IIf) (corresponding to compounds of general formula (II) wherein G³ isan oxazolidinone group) by means of a carbonylation reagent likebiscarbonyldiimidazole or a two-step process involving firstly treatmentwith di-terbutyldicarbonate to give the corresponding N—BOC derivativeand subsequent cyclization with a base like sodium hydride. Theresulting oxazolidinones of formula (IIf) can react with an alkylatingagent of formula (IIId) or (IIIb) (corresponding to compounds of generalformula (III) wherein G² is a group —CH₂Br or a group —CH₂OMs (Msstanding for a mesylate group)) in the presence of a base like sodiumhydride to give intermediates of formula (XII). Subsequent hydrolysis ofthe oxazolidinone moiety by means of a basic reagent such as an alkalinehydroxide or alkoxide like potassium trimethylsilanolate yields thecompound of formula (XI) (corresponding to compounds of general formula(II) wherein G² is a —CH(OH)—CH₂—NH—R).

In a fourth alternative the phenacyl bromides of formula (IIb) (whereinG³ is a —CO—CH₂—Br group) can react with protected amines of formula(IIIe) (corresponding to compounds of general formula (III) wherein G²is a group —CH₂—NH—P² being P² a conventional amine protecting groupsuch as a benzyl group), to give ketoamines of formula (VIII). Thisprocess can be carried out in many solvents like tetrahydrofuran ordichloromethane in the presence of an acid scavenger like a tertiaryamine as triethylamine, and at temperatures between 5 and 60° C. Thecompounds of formula (VIII) can then be reduced to yield theaminoalcohols of formula (IX). This step can be achieved in a variety ofsolvents, like tetrahydrofuran, alcohols as methanol, ethanol orisopropyl alcohol, as well as a mixture of solvents such asmethanol/tetrahydrofuran or dimethylsulfoxide/methanol, the temperaturerange being between 5° and 100° C.; more specifically between 15° and70° C. The reducing agent may be a hydride like sodium borohydride orsodium cyanoborohydride as well as hydrogen plus a hydrogenationcatalyst like palladium on charcoal. Finally the protectinggroup—usually being a benzyl group—can be removed by means ofhydrogenation with the same catalysts and conditions described above toyield the compounds of formula (XI).

In a fifth alternative protected bromohydrins of formula (IId)(corresponding to compounds of general formula (II) wherein G³ is agroup —CH(OP³)—CH₂—Br (P³ being a conventional hydroxy protecting groupsuch as a silyl ether)) can alkylate primary amines of formula (IIIf)(corresponding to compounds of general formula (III) wherein G² is agroup —CH₂NH₂) to give intermediates of formula (X). This reaction iscarried out in the presence of an acid scavenger, such as a tertiaryamine or sodium bicarbonate, in a variety of solvents like dioxane,dimethylsulfoxide or also without solvent, in a range of temperaturesbetween 60° and 140° C. The removal of the protecting group PG, usuallya silyl ether, is achieved by means of the fluoride anion, for examplein the form of a quaternary ammonium salt like tetrabutylammoniumfluoride, to give intermediates of formula (XI).

In a sixth alternative epoxides of formula (IIc) (corresponding tocompounds of general formula (II) wherein G³ is an oxyran group) canalso react with protected amines of formula (IIIe) (corresponding tocompounds of general formula (III) wherein G² is a group —CH₂—NH—P²being P² a conventional amine protecting group such as a benzyl group),to give intermediates of formula (IX). This process can be carried outin many solvents like alcohols, tetrahydrofuran or without solvents atall, in a range of temperatures between 20° and 140° C.

As a final step the compounds of formula (XI) are deprotected to thetarget compounds of formula (I) by conventional methods. When theprotecting group P¹ is a benzyl group the debenzylation is carried outwith hydrogen and a hydrogenation catalyst like palladium on charcoal.This step is achieved using a variety of solvents like alcohols,tetrahydrofuran or mixtures of them, and in neutral or slightly acidicmedia. The pressure of hydrogen lies between 6.90·10⁴ Pa and 2.76·10⁵ Paand the temperature between 10° and 30° C.

The intermediates of formulae (IIa), (IIb), (IIc), (IId), (IIe) and(IIf) may be obtained by methods well known in the literature startingfrom the phenylglyoxals of formula (IIa) or the correspondinghydrates—prepared from the corresponding acetophenones of formula (IV)(for ex., see EP 85166454, example 2; U.S. Pat. No. 4,753,962description 54 or GB 1247370, example 1).

For example the phenylethanolamines of formula (IIe) may be obtainedfollowing methods described in J. Med. Chem., 1976, 19(9), 1138,compound 19; DE 2461861, example 24. The phenacyl bromides of formula(IIb) may be obtained following methods described in Chem. Pharm. Bull.,1977, 25(6), 1368, compound II; J. Med. Chem., 1974, 17(1), 49; EP85166454, example 1). The protected bromohydrines of formula (IId) maybe obtained following methods described in US2004059116 example 9C, WO2004/011416 example 2 and WO 2004/016578 Example 1ii, The oxyranes offormula (IIc) may be obtained following methods described in WO01036375, preparation 12; J. Med. Chem., 1974, 17(1), 55).

Many of these intermediates may also exist in an enantiomerically pureform (see, for ex., Organic Process Research & Development 1998, 2, 96;Tetrahedron Lett., 1994, 35(50), 9375; WO 02070490 example 1/X; EP0147719).

As it has been explained before, the nature of the G² group in thecompounds of formula (III) depends on the coupling reaction followed toobtain compounds (I) of the present invention. Schema 2 illustrates theinterconversion of compounds of formula (III) having different G²groups.

Wherein G¹, R⁴, n, m, p, q, r, and s are as defined above.

Hydrogenation of compounds of formula (IIIa) (corresponding to compoundsof general formula (III) wherein G² is a group —CH₂—OBz) yields alcoholsof formula (IIIg) (corresponding to compounds of general formula (III)wherein G² is a group —CH₂—OH). The reaction can be carried out with acatalyst such as palladium on charcoal or platinum dioxide, in a solventsuch as ethanol, methanol, ethyl acetate or dimethylformamide, at atemperature from room temperature to 70° C., and at a pressure from1.38·10⁵ Pa to 2.76·10⁵ Pa.

Alcohols of formula (IIIg) (corresponding to compounds of generalformula (III) wherein G² is a group —CH₂—OH) can react with benzylbromide or benzyl chloride to give compounds of formula (IIIa)(corresponding to compounds of general formula (III) wherein G² is agroup —CH₂—OBz). The reaction can be carried out with a base such assodium hydroxide, potassium hydroxide or sodium hydride, optionally inthe presence of a base transfer catalyst such as tetrabutylammoniumbromide, with a solvent such as water, dimethylformamide,dimethylsulfoxide or diethylene glycol dimethyl ether, and at atemperature from 20° to 100° C.

Bromoderivatives of formula (IIId) (corresponding to compounds ofgeneral formula (III) wherein G² is a group —CH₂—Br) can be obtainedfrom alcohols of formula (IIIg) (corresponding to compounds of generalformula (III) wherein G² is a group —CH₂—OH) by reaction with lithiumbromide, phosphorus tribromide, hydrobromic acid, carbon tetrabromide orthionyl bromide, optionally with a catalyst such as triphenylphosphine,with a solvent such as pyridine, benzene, toluene, methylene chloride,chloroform, acetonitrile, ethyl ether, tetrahydrofuran or acetone, andat temperature from 0° C. to the boiling point of the solvent.

Compounds of formula (IIIa) (corresponding to compounds of generalformula (III) wherein G² is a group —CH₂—OBz) can also be obtained frombromoderivatives of formula (IIId) (corresponding to compounds ofgeneral formula (III) wherein G² is a group —CH₂—Br) and benzyl alcohol.The reaction can be carried out following the same experimentalprocedures described for the reaction of alcohols of formula (IIIg) andbenzyl bromide or benzyl chloride.

Alcohols of formula (IIIg) (corresponding to compounds of generalformula (III) wherein G² is a group —CH₂—OH) can be converted tocompounds of formula (IIIb) (corresponding to compounds of generalformula (III) wherein G² is a group —CH₂—OMs) by reaction withmethanesulfonyl chloride, in the presence of a base such astriethylamine, diisopropylethylamine or pyridine, with a solvent such asmethylene chloride, chloroform or tetrahydrofuran, and at a temperaturefrom 0° C. to the boiling point of the solvent.

Oxidation of bromoderivatives of formula (IIId) (corresponding tocompounds of general formula (III) wherein G² is a group —CH₂—Br) withan oxidant such as N-methylmorfoline N-oxide,2-dimethylamino-N,N-dimethylaniline N-oxide, pyridine N-oxide ortrimethylamine N-oxide gives compounds of formula (IIIc) (correspondingto compounds of general formula (III) wherein G² is a group —COH). Thereaction is carried out in a solvent such as dimethylformamide,dimethylsulfoxide or acetonitrile, and at a temperature from roomtemperature to the boiling point of the solvent.

Aldehydes of formula (IIIc) (corresponding to compounds of generalformula (III) wherein G² is a group —COH) can also be obtained byoxidation of alcohols of formula (IIIg) (corresponding to compounds ofgeneral formula (III) wherein G² is a group —CH₂—OH) by reaction withchromium trioxide, manganese dioxide, potassium dichromate, pyridiniumchlorochromate, oxalyl chloride in dimethylsulfoxide or Dess-Martinreagent in a solvent such as pyridine, methylene chloride, chloroform,dimethylsulfoxide or acetonitrile, and at a temperature from −78° to130° C.

Alcohols of formula (IIIg) (corresponding to compounds of generalformula (III) wherein G² is a group —CH₂—OH) can also be synthesized byreduction of aldehydes of formula (IIIc) (corresponding to compounds ofgeneral formula (III) wherein G² is a group —COH). The reaction can becarried out with a hydride such as lithium aluminum hydride, sodiumborohydride or diisobutylaluminum hydride in a solvent such as ethylether, diisopropyl ether, tetrahydrofuran or methanol, and at atemperature from room temperature to the boiling point of the solvent.

Bromoderivatives of formula (IIId) (corresponding to compounds ofgeneral formula (III) wherein G² is a group —CH₂—Br) and compounds offormula (IIIb) (corresponding to compounds of general formula (III)wherein G² is a group —CH₂—OMs) can react with potassium phtalimide togive compounds of formula (XIV). The reaction can be carried out in asolvent such as dimethylformamide, dimethylsulfoxide, acetonitrile ortetrahydrofuran, optionally with a catalyst such as(n-hexadecyl)tri-n-butylphosphonium bromide, and at a temperature fromroom temperature to the boiling point of the solvent.

The reaction of compounds of formula (IIIh) (corresponding to compoundsof general formula (III) wherein G² is a group phthalimidomethyl) withhydrazine in a solvent such as methanol, ethanol, isopropyl alcohol ortetrahydrofuran, and at a temperature from 50 to 90° C. gives amines offormula (IIIf) (corresponding to compounds of general formula (III)wherein G² is a group —CH₂—NH₂).

Amines of formula (IIIf) (corresponding to compounds of general formula(III) wherein G² is a group —CH₂—NH₂) can also be obtained by alkylationof benzyl amine with bromoderivatives of formula (IIId) (correspondingto compounds of general formula (III) wherein G² is a group —CH₂—Br) orwith compounds of formula (IIIb) (corresponding to compounds of generalformula (III) wherein G² is a group —CH₂—OMs), followed by adebenzylation process.

Alkylation of benzyl amine with compounds of formula (IIIb)(corresponding to compounds of general formula (III) wherein G² is agroup —CH₂—OMs) or with compounds of formula (IIId) (corresponding tocompounds of general formula (III) wherein G² is a group —CH₂—Br) yieldscompounds of formula (IIIe) (corresponding to compounds of generalformula (III) wherein G² is a group —CH₂—NH-Bz). The reaction can becarried out in the presence of a base such as benzyl amine,triethylamine, diisopropylethylamine or potassium carbonate, withoutsolvent or in a solvent such as dimethylformamide, acetone,tetrahydrofuran or dioxane, and at temperature from 0° C. to the boilingpoint of the solvent. The debenzylation process to give amines offormula (IIIf) can be carried out with a catalyst such as palladium oncharcoal or platinum dioxide, in a solvent such as ethanol, methanol,ethyl acetate, acetic acid or dimethylformamide, at a temperature fromroom temperature to 70° C., and at a pressure from 1.38·10⁵ Pa to2.76·10⁵ Pa.

Amines of formula (IIIe) (corresponding to compounds of general formula(III) wherein G² is a group —CH₂—NH-Bz) can also be obtained fromaldehydes of formula (IIIc) (corresponding to compounds of generalformula (III) wherein G² is a group —COH) and benzyl amine. The reactioncan be carried out with a hydride such as sodium borohydride or sodiumcyanoborohydride in a solvent such as ethyl ether, diisopropyl ether,tetrahydrofuran or methanol or a mixture of them, and at a temperaturefrom room temperature to the boiling point of the solvent.

In one alternative the compounds of formula (III)

are obtained starting from compounds of formula (XV)

wherein G¹, G², R⁴, q, r, s are as hereinabove defined and G⁴ is anhalogen atom, preferably a bromine atom or a hydroxyl group through avariety of synthetic methods which are described below:

wherein G¹, R⁴, s, r and q are as hereinabove defined; x is equal to n−1and;z is either equal to p when (IIIc2) is used as a product of formula(III) to be condensed with the adrenergic moeity or equal to p+n−1 whenproduct (XVIII) is used to be condensed with the adrenergic moeity toobtain a product of formula (I) wherein m is zero.

Compounds of formula (IIId) (corresponding to compounds of generalformula (III) wherein G² is a group —CH₂—Br) can be obtained by reactionof alcohols of formula (XVa) with dibromoderivatives of formula (XVI).The reaction can be carried out with a base such as sodium hydroxide,potassium hydroxide or sodium hydride, optionally in the presence of abase transfer catalyst such as tetrabutylammonium bromide, with asolvent such as water, dimethylformamide, dimethylsulfoxide ordiethylene glycol dimethyl ether, and at a temperature from 20° to 100°C.

Bromoderivatives of formula (IIId) (corresponding to compounds ofgeneral formula (III) wherein G² is a group —CH₂—Br) can be converted toaldehydes of formula (IIIc3) (corresponding to compounds of generalformula (III) wherein G² is a group —COH) by oxidation with an oxidantsuch as N-methylmorfoline N-oxide, 2-dimethylamino-N,N-dimethylanilineN-oxide, pyridine N-oxide or trimethylamine N-oxide. The reaction iscarried out in a solvent such as dimethylformamide, dimethylsulfoxide oracetonitrile, and at a temperature from room temperature to the boilingpoint of the solvent.

The reaction of aldehydes of formula (IIIc3) (corresponding to compoundsof general formula (III) wherein G² is a group —COH) withhaloderivatives of formula (XIX) wherein X represents a halogen atom,such as chlorine, bromine or iodine, and magnesium gives alcohols offormula (XX). The reaction can be carried out with a solvent such asethyl ether or tetrahydrofuran, and at a temperature from −78° to 80° C.

The reaction of alcohols of formula (XX) to yield ketones of formula(XXI) can be achieved by reaction with chromium trioxide, manganesedioxide, potassium dichromate, pyridinium chlorochromate, oxalylchloride in dimethylsulfoxide or Dess-Martin reagent in a solvent suchas pyridine, methylene chloride, chloroform, dimethylsulfoxide oracetonitrile, and at a temperature from −78° to 130° C.

Ketones of formula (XXI) can be transformed to compounds of formula(XXII) by reaction with a fluorinated agent such as (diethylamino)sulfur trifluoride (DAST) or [di(methoxyethyl)amino]sulfur trifluoride,optionally in the presence of a solvent such as methylene chloride,chloroform, methanol, ethanol or tetrahydrofuran, and at a temperaturefrom room temperature to the boiling point of the solvent.

Alkenes of formula (XXX) can be converted to aldehydes of formula(IIIc2) (corresponding to compounds of general formula (III) wherein G²is a group —COH) by oxidation with sodium periodate or potassiumperiodate with a catalytic amount of osmium tetroxide. The reaction canbe carried out in a solvent such as dioxane, tetrahydrofuran, methanol,ethanol, acetonitrile or water, or a mixture of them, and at atemperature from −78° C. to 100° C.

In another alternative the compounds of formula (III) wherein G¹, R⁴, s,r and q are as hereinabove defined may be obtained following the methoddepicted in Scheme 4.

The reaction of alcohols of formula (XVa) (corresponding to compounds ofgeneral formula (XV) wherein G⁴ is a group —OH) with 1,3-dibromopropanegives alkenes of formula (XXIII). The reaction can be carried outfollowing the same experimental procedure described for the synthesis ofcompounds of formula (IIId2).

Alcohols of formula (IIIg2) (corresponding to compounds of generalformula (III) wherein G² is a group —CH₂—OH, m is 0 and p+n is 2) can beobtained from alkenes of formula (XXIII) by successive reaction withborane tetrahydrofuran complex or borane-methyl sulfide complex andhydrogen peroxide, in the presence of a base such as sodium hydroxide orpotassium hydroxide in a solvent such as tetrahydrofuran, dioxane, wateror diethylene glycol dimethyl ether, and at a temperature from −78° C.to 100° C.

The conversion of compounds of formula (IIIg2) (corresponding tocompounds of general formula (III) wherein G² is a group —CH₂—OH, m is 0and p+n is 2) to aldehydes of formula (IIIc4) (corresponding tocompounds of general formula (III) wherein G² is a group —COH, m is 0and p+n is 2) can be achieved following by reaction with chromiumtrioxide, manganese dioxide, potassium dichromate, pyridiniumchlorochromate, oxalyl chloride in dimethylsulfoxide or Dess-Martinreagent in a solvent such as pyridine, methylene chloride, chloroform,dimethylsulfoxide or acetonitrile, and at a temperature from −78° to130° C.

In still another alternative the compounds of formula (IIIi)(corresponding to compounds of general formula (III) wherein G² is agroup —OH, G¹, R⁴, s, r, q and p are as hereinabove defined and m and nare both 1) may be obtained following the method depicted in Scheme 5.

Compounds of formula (IIIc5) (corresponding to compounds of generalformula (III) wherein G² is a group —CHO and m is 0) can be converted toalcohols (IIIg3) (corresponding to compounds of general formula (III)wherein G² is a group —CH₂—OH, m is 0) by reaction with a hydride suchas lithium aluminum hydride, sodium borohydride or diisobutylaluminumhydride in a solvent such as ethyl ether, diisopropyl ether,tetrahydrofuran or methanol, and at a temperature from room temperatureto the boiling point of the solvent.

Alkenes of formula (XXXI) can be obtained by reaction of alcohols offormula (IIIg3) (corresponding to compounds of general formula (III)wherein G² is a group —CH₂—OH, m is 0) with 2-nitrophenyl selenocyanateand tributylphosphine, with a solvent such as tetrahydrofuran, ethylether or dioxane, and at a temperature from room temperature to theboiling point of the solvent (see references Hart, D. J.; Kenai, K.-I.;J. Am. Chem. Soc. 1983, 105, 1255, Hart, D. J.; J. Org. Chem. 1981, 46,3575). Alcohols of formula (XVIIb) can also react with p-toluensulfonylchloride or methylsulfonyl chloride, in a solvent such astetrahydrofuran, ethyl ether, dioxane or methylene chloride, and at atemperature from room temperature to the boiling point of the solvent.The resulting intermediate reacts with a base such as potassiumhydroxide, sodium hydroxide, triethylamine or diisopropylethylamine togive compounds of formula (XXXI). The reaction can be carried outwithout solvent or with a solvent such as tetrahydrofuran, ethyl ether,dioxane or methylene chloride, and at a temperature from 20 to 250° C.

Esters of formula (XXXIII) can be obtained by reaction of alkenes offormula (XXXI) with ethyl iododifluoroacetate in the presence of a metalsuch as zinc or copper optionally with a catalyst such as nickelchloride hexahydrate and water, in a solvent such as dimethylformamide,tetrahydrofuran, dimethylsulfoxide or dioxane, and a temperature from 20to 60° C. (see ref. J. Chem. Soc. Chem. Comm., 1992, 233).

The synthesis of alcohols of formula (IIIg4) (corresponding to compoundsof general formula (III) wherein G² is a group —CH₂—OH, m is 1 and nis 1) from esters of formula (XXXIII) can be achieved by treatment witha hydride such as lithium aluminum hydride, sodium borohydride ordiisobutylaluminum hydride in a solvent such as ethyl ether, diisopropylether, tetrahydrofuran or methanol, and at a temperature from roomtemperature to the boiling point of the solvent.

Scheme 6

In another alternative method the compounds of formula (IIIg6)(corresponding to compounds of general formula (III) wherein G¹, R⁴, s,r, q and m are as hereinabove defined, p is 1 m is 2 and n is 3 may beobtained following the method depicted in Scheme 6.

Alcohols of formula (IIIg5) (corresponding to compounds of generalformula (III) wherein G² is a group —CH₂—OH and p and q are 1) can beobtained by reaction of alcohols of formula (XXXIV) withbromoderivatives of formula (XVg) (corresponding to the compounds ofgeneral formula (XV) wherein G⁴ is a Br atom). The reaction can becarried out with a base such as sodium hydroxide, potassium hydroxide orsodium hydride, optionally in the presence of a base transfer catalystsuch as tetrabutylammonium bromide, with a solvent such as water,dimethylformamide, dimethylsulfoxide or diethylene glycol dimethylether, and at a temperature from 20° to 100° C.

Aldehydes of formula (IIIc3) can be obtained from alcohols of formula(XXXV) by reaction with chromium trioxide, manganese dioxide, potassiumdichromate, pyridinium chlorochromate, oxalyl chloride indimethylsulfoxide or Dess-Martin reagent in a solvent such as pyridine,methylene chloride, chloroform, dimethylsulfoxide or acetonitrile, andat a temperature from −78° to 130° C.

Aldehydes of formula (IIIc6) (corresponding to compounds of generalformula (III) wherein G² is a —COH group, p is 1 and n is 1) can reactwith a phosphorane of formula (XXVIII) wherein R⁸ represents a C₁₋₄alkyl group and R⁹ represents a C₁₋₄ alkyl or a phenyl group to giveesters of formula (XXXVI). The reaction can be carried out in a solventsuch as methylene chloride, tetrahydrofuran, ethyl ether or toluene, andat a temperature from room temperature to the boiling point of thesolvent.

Hydrogenation of the compounds of formula (XXXVI) gives esters offormula (XXXVII). The reaction can be carried out with a catalyst suchas palladium on charcoal or platinum dioxide, in a solvent such asethanol, methanol, ethyl acetate or dimethylformamide, at a temperaturefrom room temperature to 70° C., and at a pressure from 1.38·10⁸ Pa to2.76·10⁵ Pa.

Alcohols of formula (IIIg6) (corresponding to compounds of generalformula (III) wherein G² is a group —CH₂—OH, p is 1 and n is 3) can beobtained by treatment of esters of formula (XXXVII) with a hydride suchas lithium aluminum hydride, sodium borohydride or diisobutylaluminumhydride in a solvent such as ethyl ether, diisopropyl ether,tetrahydrofuran or methanol, and at a temperature from room temperatureto the boiling point of the solvent.

In another alternative method the compounds of formula (III) whereinG¹and R⁴ are as hereinabove defined, p is 1, r is zero, n is 3, q+s is 3and G² is a group —CH₂—OH may be obtained following the method depictedin Scheme 7.

wherein X represents a halogen atom, R⁸ represents a C₁₋₄ alkyl groupand R⁹ represents a C₁₋₄ alkyl or a phenyl group.

Alcohols of formula (XXXIX) can be obtained by reaction of alcohols offormula (XXXIV) with haloderivatives of formula (XXXVIII). The reactioncan be carried out with a base such as sodium hydroxide, potassiumhydroxide or sodium hydride, optionally in the presence of a basetransfer catalyst such as tetrabutylammonium bromide, with a solventsuch as water, dimethylformamide, dimethylsulfoxide or diethylene glycoldimethyl ether, and at a temperature from 20° to 100° C.

Aldehydes of formula (XL) can be obtained from alcohols of formula(XXXIX) by reaction with chromium trioxide, manganese dioxide, potassiumdichromate, pyridinium chlorochromate, oxalyl chloride indimethylsulfoxide or Dess-Martin reagent in a solvent such as pyridine,methylene chloride, chloroform, dimethylsulfoxide or acetonitrile, andat a temperature from −78° to 130° C.

Aldehydes of formula (XL) can react with a phosphorane of formula(XXVIII) to give esters of formula (XLI). The reaction can be carriedout in a solvent such as methylene chloride, tetrahydrofuran, ethylether or toluene, and at a temperature from room temperature to theboiling point of the solvent.

Hydrogenation of the compounds of formula (XLI) gives esters of formula(XLII). The reaction can be carried out with a catalyst such aspalladium on charcoal or platinum dioxide, in a solvent such as ethanol,methanol, ethyl acetate or dimethylformamide, at a temperature from roomtemperature to 70° C., and at a pressure from 1.38·10⁵ Pa to 2.76·10⁵Pa.

Alcohols of formula (IIIg7) (corresponding to compounds of generalformula (III) wherein G² is a group —CH₂—OH, q+s is 3, r is 0, p is 1and n is 3) can be obtained by treatment of esters of formula (XLII)with a hydride such as lithium aluminum hydride, sodium borohydride ordiisobutylaluminum hydride in a solvent such as ethyl ether, diisopropylether, tetrahydrofuran or methanol, and at a temperature from roomtemperature to the boiling point of the solvent.

In another alternative the compounds of formula (IIIa)

wherein G¹, R⁴, n, m, p, q, r and s are as hereinabove defined(corresponding to compounds of general formula (III) wherein G2 is agroup —CH₂—O-Bz), are obtained starting from compounds of formula(XLIII)

following the method described in Scheme 8

Alcohols of formula (XLIII) can be converted to compounds of formula(IIIa) (corresponding to compounds of general formula (III) wherein G2is a group —CH₂—O-Bz) by reaction with bromoderivatives of formula (XVb)in the presence of a base such as sodium hydroxide, potassium hydroxideor sodium hydride, optionally in the presence of a base transfercatalyst such as tetrabutylammonium bromide, with a solvent such aswater, dimethylformamide, dimethylsulfoxide or diethylene glycoldimethyl ether, and at a temperature from 20° to 100° C.

The compounds of formula (XLIII) may be obtained following the syntheticmethods of schemes 9 to 10 which are described below:

In one alternative the compounds of formula (XLIIIa) wherein n and m areboth 1 may be obtained following the method depicted in Scheme 9.

Compounds of formula (XLV) can be converted to alcohols (XLVI) byreaction with a hydride such as lithium aluminum hydride, sodiumborohydride or diisobutylaluminum hydride in a solvent such as ethylether, diisopropyl ether, tetrahydrofuran or methanol, and at atemperature from room temperature to the boiling point of the solvent.

Alkenes of formula (XLVII) can be obtained by reaction of alcohols offormula (XLVI) with 2-nitrophenyl selenocyanate and tributylphosphine,with a solvent such as tetrahydrofuran, ethyl ether or dioxane, and at atemperature from room temperature to the boiling point of the solvent(see references Hart, D. J.; Kenai, K.-I.; J. Am. Chem. Soc. 1993, 105,1255; Hart, D. J.; J. Org. Chem 1981, 46, 3576).

Alcohols of formula (XLVI) can also react with p-toluensulfonyl chlorideor methylsulfonyl chloride, in a solvent such as tetrahydrofuran, ethylether, dioxane or methylene chloride, and at a temperature from roomtemperature to the boiling point of the solvent. The resultingintermediate reacts with a base such as potassium hydroxide, sodiumhydroxide, triethylamine or diisopropylethylamine to give compounds offormula (XLVII). The reaction can be carried out without solvent or witha solvent such as tetrahydrofuran, ethyl ether, dioxane or methylenechloride, and at a temperature from 20 to 250° C.

Esters of formula (XLVIII) can be obtained by reaction of alkenes offormula (XLVII) with ethyl iododifluoroacetate (XXXII) in the presenceof a metal such as zinc or copper optionally with a catalyst such asnickel chloride hexahydrate and water, in a solvent such asdimethylformamide, tetrahydrofuran, dimethylsulfaxide or dioxane, and atemperature from 20 to 60° C. (see ref. J. Chem. Soc. Chem. Comm., 1992,233).

The synthesis of alcohols of formula (XLIIIa) from esters of formula(XLVIII) can be achieved by treatment with a hydride such as lithiumaluminum hydride, sodium borohydride or diisobutylaluminum hydride in asolvent such as ethyl ether, diisopropyl ether, tetrahydrofuran ormethanol, and at a temperature from room temperature to the boilingpoint of the solvent.

In another alternative method the compounds of formula (XLIIIc) whereinm is as hereinabove defined and R⁵ represents a C₁₋₄ alkyl group or aphenyl group, may be obtained following the method depicted in Scheme10.

Alcohols of formula (XLIIIb) can be obtained by reaction of alcohols offormula (XXXIV) with benzyl bromide. The reaction can be carried outwith a base such as sodium hydroxide, potassium hydroxide or sodiumhydride, optionally in the presence of a base transfer catalyst such astetrabutylammonium bromide, with a solvent such as water,dimethylformamide, dimethylsulfoxide or diethylene glycol dimethylether, and at a temperature from 20° to 100° C.

Aldehydes of formula (XLIX) can be obtained from alcohols of formula(XLIIIb) by reaction with chromium trioxide, manganese dioxide,potassium dichromate, pyridinium chlorochromate, oxalyl chloride indimethylsulfoxide or Dess-Martin reagent in a solvent such as pyridine,methylene chloride, chloroform, dimethylsulfoxide or acetonitrile, andat a temperature from −78° to 130° C.

Aldehydes of formula (XLIX) can react with a phosphorane of formula(XXVIII) to give esters of formula (L). The reaction can be carried outin a solvent such as methylene chloride, tetrahydrofuran, ethyl ether ortoluene, and at a temperature from room temperature to the boiling pointof the solvent.

Hydrogenation of the compounds of formula (L) gives esters of formula(LI). The reaction can be carried out with a catalyst such as palladiumon charcoal or platinum dioxide, in a solvent such as ethanol, methanol,ethyl acetate or dimethylformamide, at a temperature from roomtemperature to 70° C., and at a pressure from 1.38·10⁵ Pa to 2.76·10⁵Pa.

Alcohols of formula (XLIIIc) can be obtained by treatment of esters offormula (LI) with a hydride such as lithium aluminum hydride, sodiumborohydride or diisobutylaluminum hydride in a solvent such as ethylether, diisopropyl ether, tetrahydrofuran or methanol, and at atemperature from room temperature to the boiling point of the solvent.

The compounds of formula (XV) may be obtained following the syntheticmethods of schemes 11 to 13 which are described below:

wherein s and R⁴ are as hereinabove defined, G¹ is selected from

hydrogen or halogen atoms or groups selected from C₁₋₄ alkyl, C₁₋₄alkoxy, S—R⁵, SO—R⁵ and SO₂—R⁵ wherein R⁵ is a C₁₋₄ alkyl or C₃₋₆cycloalkyl; R⁴ is selected from hydrogen atom, halogen atoms and C₁₋₄alkyl groups and R⁷ is a C₁₋₄ alkyl group.

Compounds of formula (XXV) can be transformed to compounds of formula(XXVI) by reaction with a fluorinated agent such as (diethylamino)sulfur trifluoride (DAST) or [di(methoxyethyl)amino]sulfur trifluoride,optionally in the presence of a solvent such as methylene chloride,chloroform, methanol, ethanol or tetrahydrofuran, and at a temperaturefrom room temperature to the boiling point of the solvent.

Alcohols of formula (XVa) can be obtained by treatment of esters offormula (XXVI) with a hydride such as lithium aluminum hydride, sodiumborohydride or diisobutylaluminum hydride in a solvent such as ethylether, diisopropyl ether, tetrahydrofuran or methanol, and at atemperature from room temperature to the boiling point of the solvent.

Alcohols of formula (XVa2) wherein x is at least 1 can be converted toaldehydes of formula (XVc2) by reaction with chromium trioxide,manganese dioxide, potassium dichromate, pyridinium chlorochromate,oxalyl chloride in dimethylsulfoxide or Dess-Martin reagent in a solventsuch as pyridine, methylene chloride, chloroform, dimethylsulfoxide oracetonitrile, and at a temperature from −78° to 130° C.

Aldehydes of formula (XVc2) can be transformed to alkenes of formula(XXVII) with Tebbe reagent or methyltriphenylphosphonium bromide in thepresence of a base such as sodium hydride or sodium amide with a solventsuch as tetrahydrofuran, dioxane, methylene chloride ordimethylsulfoxide, and at a temperature from −78° C. to 80° C.

Alcohols of formula (XVa3) can be obtained from alkenes of formula(XXVII) by reaction with borane tetrahydrofuran complex or borane-methylsulfide complex with hydrogen peroxide, in the presence of a base suchas sodium hydroxide or potassium hydroxide in a solvent such astetrahydrofuran, dioxane, water or diethylene glycol dimethyl ether, andat a temperature from −78° C. to 100° C.

Alcohols of formula (XVa3) can be converted to aldehydes of formula(XVc3) by reaction with chromium trioxide, manganese dioxide, potassiumdichromate, pyridinium chlorochromate, oxalyl chloride indimethylsulfoxide or Dess-Martin reagent in a solvent such as pyridine,methylene chloride, chloroform, dimethylsulfoxide or acetonitrile, andat a temperature from −78° to 130° C.

Aldehydes of formula (XVc3) can react with a phosphorane of formula(XXVIII) wherein R⁸ is a C₁₋₄ alkyl group and R⁹ is C₁₋₄ alkyl or phenylgroup to give esters of formula (XXIX). The reaction can be carried outin a solvent such as methylene chloride, tetrahydrofuran, ethyl ether ortoluene, and at a temperature from room temperature to the boiling pointof the solvent.

Hydrogenation of the compounds of formula (XXIX) gives esters of formula(XXX). The reaction can be carried out with a catalyst such as palladiumon charcoal or platinum dioxide, in a solvent such as ethanol, methanol,ethyl acetate or dimethylformamide, at a temperature from roomtemperature to 70° C., and at a pressure from 1.38·10⁵ Pa to 2.76·10⁵Pa.

Alcohols of formula (XVa4) can be obtained by treatment of esters offormula (XXI) with a hydride such as lithium aluminum hydride, sodiumborohydride or diisobutylaluminum hydride in a solvent such as ethylether, diisopropyl ether, tetrahydrofuran or methanol, and at atemperature from room temperature to the boiling point of the solvent.

Esters of formula (LVIII) can be obtained by reaction of phenyliodidesof formula (LVI) with alkyl iodotetrafluoropropionate (LVII) wherein R⁷is a C₁₋₄ alkyl group in the presence of copper optionally with acatalyst such as a palladium complex, in a solvent such asdimethylformamide, tetrahydrofuran, dimethylsulfoxide or dioxane, and atemperature from 20 to 60° C. (see ref. Journal of Fluorine Chemistry,2004, 125 (5), 763-765).

Alcohols of formula (XVa5) can be obtained by treatment of esters offormula (LVIII) with a hydride such as lithium aluminum hydride, sodiumborohydride or diisobutylaluminum hydride in a solvent such as ethylether, diisopropyl ether, tetrahydrofuran or methanol, and at atemperature from room temperature to the boiling point of the solvent.

The alcohols of formula (XVa6) (corresponding to compounds of generalformula (XV) wherein s is 0, r is 1, q is 2, and G⁴ is a group —OH) andG¹ and R⁴ are as hereinabove defined, can be obtained following scheme14.

The 3-chloro-1-phenylpropan-1-ones (LIX) are reacted with sodium orpotassium acetate and sodium or potassium iodide in a solvent such asglacial acetic acid and a temperature from room temperature to theboiling point of the solvent to yield the compounds of formula (LX).

Subsequent reaction of the compounds of formula (LX) with a fluorinatingagent such as (diethylamino) sulfur trifluoride (DAST) or[di(methoxyethyl)amino]sulfur trifluoride (DEOXOFLUOR®), optionally inthe presence of a solvent such as methylene chloride, chloroform,methanol, ethanol or tetrahydrofuran, and at a temperature from roomtemperature to the boiling point of the solvent yields the compounds offormula (XVd).

The hydrolysis of the ester group in the compounds of formula (XVd) inan aqueous solution of sodium hydroxide, potassium hydroxide or sodiumcarbonate, optionally in the presence of a solvent such as ethanol,methanol or isopropyl alcohol, and at a temperature from roomtemperature to the boiling point of the solvent, yields the alcohols offormula (XVa6).

The alcohols of formula (XVa7) (corresponding to compounds of generalformula (XV) wherein q, r and s have all the value of 1, and G⁴ is agroup —OH) and G¹ and R⁴ are as hereinabove defined, can be obtainedfollowing scheme 15.

The 1-phenylethanones (LXI) are reacted with bromo(difluoro)acetate inthe presence of Zn in a solvent such as tetrahydrofuran, dioxane orethyl ether and at temperature from room temperature to the boilingpoint of the solvent.

The resulting compounds (LXII) are then reacted with CS₂ in a solventsuch as DMSO, DMF, tetrahydrofuran or dioxane and a temperature fromroom temperature to 60° C. and inert atmosphere to yield a thioacid (notshown) which upon reaction with methyl iodide or dimethylsulfate at roomtemperature yields the compounds of formula (LXIII).

In a subsequent step the compounds of formula (LXIII) are reacted with adiphenylphosphine oxide and tBuOOtBu (ditertbutyl peroxide) in a solventsuch as tetrahydrofuran, dioxane or ethyl ether and at temperature fromroom temperature to the boiling point of the solvent to yield thecompounds of formula (LXIV).

In a final step the compounds of formula (LXIV) are reacted with ahydride such as lithium aluminum hydride, sodium borohydride ordiisobutylaluminum hydride in a solvent such as ethyl ether, diisopropylether, tetrahydrofuran or methanol, and at a temperature from roomtemperature to the boiling point of the solvent to yield the alcohols(XVa7).

Compounds of formula (IIIb) wherein m, n, p, q, r and s are ashereinabove defined, R³ is a hydantoino group and R⁴=hydrogen atom orC₁₋₄ alkyl, can be obtained as shown in Scheme 16.

Amines of formula (IIIa3) can be obtained from compounds of formula(IIIa2) by reaction with lithium bis(trimethylsilyl)amide, sodiumbis(trimethylsilyl)amide or tert-butyl carbamate. The reaction can becarried out with a base such as sodium ethoxide, potassium carbonate orsodium phenoxide, with a catalytic amount of a phosphine such asditert-butylphosphine, tri-o-tolylphosphine or triphenylphosphine and apalladium catalyst such as bis(dibenzylideneacetone)palladium ortris(dibenzylideneacetone)-dipalladium(0), with a solvent such astetrahydrofuran, dioxane, toluene or benzene, and at a temperature from−78° C. to 80° C.

Amines of formula (IIIa3) can be converted to compounds of formula(IIIa4) by reaction with isocyanates of formula (LII) in a solvent suchas toluene, benzene or dioxane, and at a temperature from roomtemperature to the boiling point of the solvent.

Saponification of compounds of formula (IIIa4) gives compounds offormula (IIIa5). The reaction can be carried out with a base such assodium hydroxide or potassium hydroxide, with a solvent such asmethanol, ethanol, water or a mixture of them, and at a temperature fromroom temperature to the boiling point of the solvent.

Compounds of formula (IIIa6) can be obtained by cyclization of compoundsof formula (IIIa5) with an acid such as hydrochloric acid or aceticacid, with a solvent such as methanol, acetic acid, ethanol or water ora mixture of them, and at a temperature from room temperature to theboiling point of the solvent.

Compounds of formula (IIIa6) can be modified to the correspondingalcohol, bromoderivative, mesylate, aldehyde or aminoderivative,following the same pathway shown in Scheme 2.

Compounds wherein R⁴, m, n, p, q, r and s are as hereinabove defined andR³ is an amido group and G² is either a —CH₂—Br group (IIId) or abenzyloxymethyl (IIIa) can be obtained as shown in Scheme 17.

Compounds of formula (IIIa8) or (IIId4) can be obtained from compoundsof formula (IIIa7) or (IIId3) by procedures know described in theliterature (Meyers A. I., Temple D. L., Haidukewych E. D., J Org Chem,1974, 39(18), 2787; Svenson R. Gronowitz S., Chem Ser, 1982, 19, 149;Meyers A. I., Lutomski K. A., Synthesis, 1983, 105).

The reaction of compounds of formula (IIIa8) or (IIId4) with phosphorusoxychloride gives nitriles of formula (IIIa9) or (IIId5). The reactioncan be carried out in the presence of a base such as pyridines,triethylamine or diisopropylethylamine, with a solvent such as pyridine,benzene or toluene, and at temperature from room temperature to theboiling point of the solvent.

The synthesis of amides of formula (IIIa10) or (IIId6) from nitriles offormula (IIIa9) or (IIId5) can be achieved by reaction with hydrogen inthe presence of a catalyst such as Nickel-Raney, palladium on charcoalor platinum dioxide, with a solvent such as methanol, ethanol, isopropylalcohol or ethyl acetate, at a temperature from room temperature to 60°C., and at a pressure from 1.38·10⁵ Pa to 2.76·10⁵ Pa.

Nitriles of formula (IIIa9) or (IIId5) can also react with concentratedsulfuric acid to give amides of formula (IIIa10) or (IIId6). Thereaction can be carried out without solvent or with a solvent such asmethanol, ethanol or isopropyl alcohol, and at a temperature from roomtemperature to 150° C.

The reaction of nitriles of formula (IIIa9) or (IIId5) with hydrogenperoxide can also afford amides of formula (IIIa10) or (IIId6). Thereaction can be carried out in the presence of a base such as sodiumhydroxide, potassium hydroxide or potassium carbonate, in a solvent suchas methanol, ethanol, isopropyl alcohol, dimethylsulfoxide or acetone,and at a temperature from −20° to 120° C.

Derivatives of formula (IIIa10) can be converted to the correspondingalcohol, mesylate, aldehyde or amino derivative, following the samepathway shown in Scheme 2.

Compounds of formula (I) wherein R³ is an ureic group, P¹ is an oxygenprotecting group such as benzyl group, R⁴ is a hydrogen atom or a C₁₋₄alkyl group and R¹, R², n, m, p, q, r, and s are as hereinabove defined,can be obtained as shown in Scheme 18.

Amines of formula (LIV) can be obtained from compounds of formula (LIII)by reaction with lithium bis(trimethylsilyl)amide, sodiumbis(trimethylsilyl)amide or tert-butyl carbamate, with a base such assodium ethoxide, potassium carbonate or sodium phenoxide, with acatalytic amount of a phosphine such as ditert-butylphosphine,tri-o-tolylphosphine or triphenylphosphine and a palladium catalyst suchas bis(dibenzylideneacetone)palladium ortris(dibenzylideneacetone)-dipalladium(0), with a solvent such astetrahydrofuran, dioxane, toluene or benzene, and at temperature from−78° C. to 80° C.

Amines of formula (LIV) can be converted to ureas of formula (LV) byreaction with potassium cyanate in the presence of an acid such ashydrochloric acid or acetic acid in water, and at a temperature from 0°C. to 100° C.

Compounds of formula (III) wherein R³ is a group R⁵—SO— or R⁶—SO₂— andG², R⁴, n, m, p, q, r, and s are as hereinabove defined, can be obtainedas shown in Scheme 19.

Thioethers of general formula (IIIk) can be converted to sulfoxides ofgeneral formula (IIIm) and to sulfones of general formula (IIIn) byreaction with an oxidizing agent such as 3-chloroperoxybenzoic acid,magnesium monoperoxyphthalate or potassium peroxymonosulfate, in asolvent such as acetone, methylene chloride, methanol or ethanol, or amixture of them, and at a temperature of from 10° C. to 40° C.

Conversion of sulfoxides of formula (IIIo) into compounds of formula(IIIp) can be carried out with sodium acetate and acetic anhydride, at atemperature from 100° to 160° C.

Oxidation of compounds of formula (IIIp) gives sulfones of formula(IIIq). The reaction can be achieved using an oxidizing agent such as3-chloroperoxybenzoic acid, magnesium monoperoxyphthalate or potassiumperoxymonosulfate, in a solvent such as acetone, methylene chloride,methanol or ethanol, or a mixture of them, and at a temperature of from10° C. to 40° C.

Sulfones of formula (IIIq) can be converted to compounds of formula(IIIr). The reaction can be carried out with a base such as sodiumhydroxide or potassium hydroxide, in a solvent such as tetrahydrofuran,methanol or ethanol, or a mixture of them, and at a temperature from 0°C. to 80° C.

Reaction of compounds of formula (IIIr) with hydroxylamine-o-sulfonicacid gives sulfonamides of formula (IIIs). The process can be carriedout in a solvent such as acetic acid or water, in the presence of sodiumacetate, and at a temperature from 0° C. to 100° C.

Sulfonamides of formula (IIIs) can also be obtained from sulfones offormula (IIIt). In a first step, sulfones of formula (IIIt) react with amagnesium derivative such as methylmagnesium chloride or ethyl magnesiumchloride in the presence of a borane such as triethyl or tributylboraneand at room temperature. The final sulfonamide is achieved in a solventsuch as acetic acid or water, in the presence of sodium acetate, and ata temperature from 0° C. to 100° C.

EXAMPLES

General. Reagents, starting materials, and solvents were purchased fromcommercial suppliers and used as received. Concentration refers toevaporation under vacuum using a Büchi rotatory evaporator. Reactionproducts were purified, when necessary, by flash chromatography onsilica gel (40-63 μm) with the solvent system indicated. Spectroscopicdata were recorded on a Varian Gemini 300 spectrometer and a VarianInova 400 spectrometer. Melting points were recorded on a Büchi 535apparatus.

Intermediate 1. Ethyl 2,2-difluoro-4-phenylbutanoate

To a cooled solution of ethyl 2-oxo-4-phenylbutanoate (1.0 g, 4.85 mmol)in methylene chloride (10 mL) was added DAST (1.6 ml, 12.1 mmol). Themixture was stirred at room temperature overnight. The crude reactionwas diluted with methylene chloride (10 mL), washed with saturatedsolution of sodium bicarbonate (2×10 mL) and water (10 mL), dried(Na₂SO₄), and the solvent removed under reduced pressure. The titlecompound was obtained as brown oil (1.02 g, 91%).

Intermediate 2. 2,2-Difluoro-4-phenylbutan-1-ol

To a cooled solution of intermediate 1 (1.0 g, 4.45 mmol) intetrahydrofuran (15 mL) was added lithium aluminum hydride (0.22 g, 5.78mmol). The mixture was stirred at room temperature overnight. To thecrude reaction was added water (0.3 mL), 4N sodium hydroxide (0.3 mL)and water (0.9 mL). The resulting solid was filtered through Celite andthe solvent removed under reduced pressure. The residue was diluted withmethylene chloride (20 mL) and washed with water (10 mL), 2Nhydrochloric acid (2×10 mL) and water (10 mL), dried (Na₂SO₄), andconcentrated. The title compound was obtained as brown oil (0.6 g, 72%).

¹H-NMR (300 MHz, CDCl₃): 2.10-2.35 (m, 2H); 2.75-2.85 (m, 2H): 3.75 (t,J_(F-H)=14.0 Hz, 2H); 7.15-7.25 (m, 3H); 7.25-7.35 (m, 2H).

Intermediate 3. {4-[(6-Bromohexyl)oxy]-3,3-difluorobutyl}benzene

To a solution of Intermediate 2 (0.60 g, 3.22 mmol) in 1,6-dibromohexane(1.74 mL, 11.27 mmol) was added tetrabutylammonium bromide (21 mg, 0.064mmol) and 50% sodium hydroxide (1.2 mL). The mixture was stirred at roomtemperature overnight. The crude reaction was diluted with n-hexane (20mL), washed with water (2×10 mL), dried (Na₂SO₄), and the solventremoved under reduced pressure. The title compound was obtained (2.1 g,52% purity) and was used in the next step without further purification.

¹H-NMR (300 MHz, CDCl₃): 1.30-1.50 (m, 4H); 1.50-1.65 (m, 2H): 1.70-1.90(m, 2H); 2.15-2.35 (m, 2H); 2.75-2.90 (m, 2H); 3.35-3.45 (m, 2H);3.45-3.70 (m, 4H); 7.15-7.25 (m, 3H); 7.25-7.35 (m, 2H).

Intermediate 4.(R,S)-2-{[6-(2,2-Difluoro-4-phenylbutoxy)hexyl]amino}-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)ethanol

To a solution of Intermediate 3 (0.385 g, 0.57 mmol of pure compound) indimethylformamide (15 mL) was added potassium carbonate (0.31 g, 2.28mmol) and (R,S)-2-amino-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)ethanol(0.26 g, 1.14 mmol). The mixture was stirred at 80° C. for 66 hours. Thecrude reaction was filtered and the solvent removed under reducedpressure. The residue was purified by column chromatography with silicagel, eluting with methylene chloride/methanol (from 982 to 95:5), togive(R,S)-2-{[6-(2,2-difluoro-4-phenylbutoxy)hexyl]amino}-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)ethanol(0.2 g, 71%) as brown oil.

MS (M+): 491

Example 1(R,S)-4-(2-{[6-(2,2-Difluoro-4-phenylbutoxy)hexyl]amino}-1-hydroxy-ethyl)-2-(hydroxymethyl)phenol

A solution of Intermediate 4 (0.20 g, 0.4 mmol) in a mixture of aceticacid (10 mL) and water (2 mL) was heated at 70° C. for 3 hours. Thesolvent was removed under reduced pressure. The resulting oil waspurified by column chromatography with silica gel, eluting withmethylene chloride/methanol/ammonium hydroxide (80:15:1.5) to give(R,S)-4-(2-{[6-(2,2-difluoro-4-phenylbutoxy)hexyl]amino}-1-hydroxy-ethyl)-2-(hydroxymethyl)phenol(104 mg, 57%) as oil.

¹H-NMR (400 MHz, dimethylsulfoxide-D6), 1.25-1.31 (m, 4H); 1.34-1.41 (m,2H): 1.47-1.54 (m, 2H); 2.12-2.25 (m, 2H); 2.54-2.57 (m, 4H); 2.71-2.75(m, 2H); 3.47 (t, J=6.4 Hz, 2H); 3.66 (t, J_(F-H)=13.3 Hz, 2H);4.45-4.50 (m, 4H); 4.90-4.92 (m, 1H); 4.99 (bs, 1H); 6.68 (d, J=8.3 Hz,1H); 6.97 (dd, J₁=8.3 Hz, J₂=2.1 Hz, 1H); 7.17-7.31 (m, 6H); 9.14 (bs,1H).

MS (M+): 451.

Intermediate 6. Ethyl difluoro(phenyl)acetate

Obtained from ethyl(phenyl)(oxo)acetate (7.5 mL, 47 mmol) by theprocedure described in Intermediate 1. Purification by columnchromatography with silica gel and n-hexane/ethyl acetate (from puren-hexane to 10:1) as eluent gave the title compound (13.2 g, 70%) asoil.

¹H-NMR (300 MHz, CDCl₃): 1.30 (t, J=7.1 Hz, 3H); 4.3 (q, J=7.1 Hz, 2H);7.43-7.51 (m, 3H); 7.61-7.63 (m, 2H).

Intermediate 6. 2,2-Difluoro-2-phenylethanol

Obtained from Intermediate 5 (13.2 g, 66 mmol) by the proceduredescribed in Intermediate 2. The title compound was obtained (6.88 g,66%) as oil.

¹H-NMR (300 MHz, CDCl₃): 4.00 (t, J_(F-H)=13.5 Hz, 2H); 7.45-7.48 (m,3H); 7.50-7.54 (m, 2H),

Intermediate 7. {2-[(6-Bromohexyl)oxy]-1,1-difluoroethyl}benzene

Obtained from Intermediate 6 (6.88 g, 43.5 mmol) by the proceduredescribed in Intermediate 3. Purification by column chromatography withsilica gel and n-hexane/ethyl acetate (10:1) as eluent gave the titlecompound (10.9 g, 78%) as oil.

¹H-NMR (300 MHz, CDCl₃):1.40-1.60 (m, 2H); 1.78-1.90 (m, 4H); 3.36-3.44(m, 4H); 3.52 (t, J=6.5 Hz, 2H); 3.84 (t, J_(F-H)=13.2 Hz, 2H);7.43-7.46 (m, 3H); 7.50-7.54 (m, 2H).

Intermediate 8.2-[6-(2,2-Difluoro-2-phenylethoxy)hexyl]-1H-isoindole-1,3(2H)-dione

To a solution of Intermediate 7 (10.9 g, 34 mmol) in dimethylformamide(23 mL) was added potassium phthalimide (7.56 g, 40.8 mmol) and acatalytic amount of (n-hexadecyl)tri-n-butylphosphonium bromide. Themixture was heated at 70° C. for 3 hours. The solvent was removed underreduced pressure. Purification by column chromatography with silica gel,eluting with methylene chloride yielded the title compound (6.41 g, 49%)as oil.

¹H-NMR (300 MHz, CDCl₃): 1.28-1.33 (m, 4H); 1.51-1.56 (m, 2H); 1.62-1.66(m, 2H); 3.50 (t, J=6.5 Hz, 2H); 3.63-3.68 (m, 2H); 3.82 (t,J_(F-H)=13.2 Hz, 2H); 7.42-7.44 (m, 3H); 7.49-7.52 (m, 2H); 7.69-7.72(m, 2H); 7.83-7.86 (m, 2H).

Intermediate 9. [6-(2,2-Difluoro-2-phenylethoxy)hexyl]amine

To a solution of Intermediate 8 (6.41 g, 16.5 mmol) in ethanol (50 ml)was added hydrazine monohydrate (12 mL, 247 mmol). The mixture wasstirred at room temperature overnight, concentrated, and the residue wastriturated with isopropyl alcohol. The resulting solid was filtered andthe solvent removed under reduced pressure. The residue was purified bycolumn chromatography with silica gel, eluting with methylenechloride/ethanol/ammonium hydroxide (80:8:1) to give the title compound(2.31 g, 54%) as oil.

¹H-NMR (300 MHz, CDCl₃): 1.27-1.32 (m, 4H); 1.39-1.44 (m, 2H); 1.53-1.58(m, 2H); 2.66 (t, J=6.9 Hz, 2H); 3.52 (t, J=6.5 Hz, 2H); 3.84 (t,J_(F-H)=13.2 Hz, 2H); 7.43-7.46 (m, 3H); 7.51-7.54 (m, 2H).

Intermediate 10.(R,S)-1-[4-(Benzyloxy)-3-(hydroxymethyl)phenyl]-2-{[6-(2,2-difluoro-2-phenylethoxy)hexyl]amino}ethanol

A solution of Intermediate 9 (0.71 g, 2.77 mmol) and4-(benzyloxy)-3-(hydroxymethyl)phenyl](oxo)acetaldehyde (0.75 g, 2.77mmol) in tetrahydrofuran (8 mL) and methanol (8 mL) was stirred at roomtemperature for 1 hour. The solution was cooled to 0° C. and sodiumborohydride (0.25 g, 6.65 mmol) was slowly added. The reaction mixturewas stirred at room temperature for 2.5 hours. Water was added (2 mL)and the solvent removed under reduced pressure. The residue was treatedwith methylene chloride (20 mL) and water. The organic layer was washedwith water (2×10 mL), saturated solution of sodium bicarbonate (2×10 mL)and brine (10 mL), dried (Na₂SO₄) and the solvent removed under reducedpressure.(R,S)-1-[4-(Benzyloxy)-3-(hydroxymethyl)phenyl)-2-{[6-(2,2-difluoro-2-phenylethoxy)hexyl]amino}ethanolwas obtained (1.43 g, 100%) as oil.

¹H-NMR (300 MHz, CDCl₃): 1.25-1.35 (m, 4H); 1.40-1.60 (m, 5H); 2.57-2.64(m, 3H); 2.82-2.84 (m, 1H); 3.53 (d, J=5.2 Hz, 2H); 3.79-3.88 (m, 2H);4.60-4.70 (m, 1H); 4.73 (s, 2H); 5.12 (s, 2H); 5.30-5.32 (m, 1H); 6.92(d, J=8.2 Hz, 1H); 7.26-7.50 (m, 10H).

Example 2(R,S)-4-(2-{[6-(2,2-Difluoro-2-phenylethoxy)hexyl]amino}-1-hydroxy-ethyl)-2-(hydroxymethyl)phenol

To a solution of Intermediate 10 (1.43 g, 2.78 mmol) in methanol (100mL) was added palladium on charcoal (150 mg). The mixture washydrogenated at 20 psi for 6 hours. The catalyst was filtered throughCelite and the solvent removed under reduced pressure. The resulting oilwas purified by column chromatography eluting with methylenechloride/ethanol/ammonium hydroxide (40:8:1) to give(R,S)-4-(2-{[6-(2,2-difluoro-2-phenylethoxy)hexyl]amino}-hydroxy-ethyl)-2-(hydroxymethyl)phenol(0.75 g, 64%) as oil.

¹H-NMR (400 MHz, Cl₃CD): 1.25-1.33 (m, 4H); 1.41-1.47 (m, 2H); 1.50-1.56(m, 2H); 2.51-2.74 (m, 4H); 3.51 (t, J==6.7 Hz, 2H); 3.79 (bs, 4H); 3.84(t, J_(F-H)=13.1 Hz, 2H); 4.54 (dd, J₁=8.8 Hz, J₂=3.7 Hz, 1H); 4.72 (s,2H); 6.77 (d, J=8.2 Hz, 1H); 6.93 (s, 1H); 7.08 (dd, J₁=8.2 Hz, J₂=2.0Hz, 1H); 7.42-7.44 (m, 3H); 7.50-7.52 (m, 2H).

MS (M+): 423.

Intermediate 11. [4-(Allyloxy)butyl]benzene

To a solution of 4-phenylbutan-1-ol (0.60 g, 3.99 mmol) in1,3-dibromopropane (2.14 mL, 10.60 mmol) was added tetrabutylammoniumbromide (20 mg, 0.064 mmol) and 50% sodium hydroxide (1.5 mL). Themixture was stirred at room temperature overnight. The crude reactionwas diluted with n-hexane (20 mL) and washed with water (2×10 mL), dried(Na₂SO₄), and the solvent removed under reduced pressure. The titlecompound (1.90 g, 92% purity) was obtained by distillation of theresidue under reduced pressure and was used in the next step withoutfurther purification.

¹H-NMR (300 MHz, CDCl₃): 1.50-1.80 (m, 4H); 2.50-2.70 (m, 2H); 3.35-3.45(m, 2H); 3.90-4.00 (m, 2H); 5.10-5.35 (m, 2H); 5.80-6.00 (m, 1H);7.15-7.20 (m, 3H); 7.20-7.35 (m, 2H).

Intermediate 12. 3-(4-Phenylbutoxy)propan-1-ol

A solution of Intermediate 11 (0.40 g, 2.10 mmol) in THF (5 mL) wascooled to 0° C. A 0.5 M solution of BBN (5 mL, 2.52 mmol) in THF wasadded, and the resulting mixture was stirred 1 hour at 0° C. and 2 hoursat room temperature. A solution of 2M NaOH (1 mL) and hydrogen peroxide(1 mL, 35%) was successively added and the mixture stirred 1 hour atroom temperature. The solution was then concentrated and the residuedissolved in ether (25 mL), washed with water (2×15 mL) and brine (5mL), dried (Na₂SO₄) and the solvent removed under reduced pressure.Purification of the residue by column chromatography on silica gel(hexane/AcOEt, 6:1) afforded the title compound (0.24 g, 55%) as oil.

¹H-NMR (300 MHz, CDCl₃): 1.50-1.75 (m, 4H); 1.75-1.90 (m, 2H); 2.55-2.70(m, 2H); 3.35-3.50 (m, 2H): 3.60 (t, J=6.0 Hz, 2H); 3.70-3.85 (m, 2H);7.15-7.20 (m, 3H); 7.20-7.35 (m, 2H).

Intermediate 13. 3-(4-Phenylbutoxy)propionaldehyde

To a solution of Intermediate 12 (1.0 g, 4.8 mmol) in CH₂Cl₂ (20 mL) wasadded Dess-Martin periodinane (2.4 g, 5.76 mmol) and the reaction wasstirred 2 hours at room temperature. The solution was then diluted withCH₂Cl₂ (40 mL), washed with water (2×20 mL), saturated solution ofsodium bicarbonate (2×20 mL), and water (20 mL), dried (Na₂SO₄), andconcentrated. The residue was purified by column chromatography(methylene chloride/acetone, 20:1) to afford the title compound (550 mg,58%) as oil.

¹H-NMR (300 MHz, CDCl₃): 1.50-1.75 (m, 4H); 2.55-2.75 (m, 4H); 3.35-3.50(m, 2H); 3.70-3.80 (m, 2H); 7.15-7.20 (m, 3H); 7.20-7.35 (m, 2H); 9.80(bs, 1H).

Intermediate 14. 1-(4-Phenylbutoxy)hept-6-en-3-ol

A solution of Intermediate 13 (0.55 g, 2.66 mmol) in THF (5 mL) wascooled to −30° C. To this solution a 0.5 M solution of3-butenylmagnesium bromide (5.8 mL, 2.92 mmol) in THF was added, and theresulting mixture was stirred 2 hours at −30° C. The reaction wasallowed to reach room temperature; acetic acid (0.1 mL) was added andconcentrated. Purification by column chromatography with silica gel andmethylene chloride/acetone (20:1) as eluent afforded the title compound(410 mg, 54%) as oil.

¹H-NMR (300 MHz, CDCl₃): 1.40-1.80 (m, 8H); 2.00-2.15 (m, 2H); 2.55-2.70(m, 2H); 3.15-3.25 (bs, 1H); 3.35-3.50 (m, 2H); 3.75-3.85 (m, 1H);4.90-5.10 (m, 2H); 5.75-2.95 (m, 1H); 7.15-7.20 (m, 3H); 7.20-7.35 (m,2H).

Intermediate 15. 1-(4-Phenylbutoxy)hept-6-en-3-one

Obtained from Intermediate 14 (0.41 g, 1.56 mmol) by the proceduredescribed for the Intermediate 13. Purification by column chromatographywith silica gel and methylene chloride/acetone (20:1) as eluent gave thetitle compound (0.36 g, 88%) as oil.

Intermediate 16. {4-[(3,3-Difluorohept-6-en-1-yl)oxy]butyl}benzene

To a cooled solution of Intermediate 15 (0.36 g, 1.36 mmol) in methylenechloride (1 mL) was added DAST (0.8 ml, 6.0 mmol). The mixture wasstirred at room temperature overnight. The crude reaction was dilutedwith methylene chloride (10 mL), washed with saturated solution ofsodium bicarbonate (2×5 mL) and water (5 mL), dried (Na₂SO₄), and thesolvent removed under reduced pressure. The residue was purified bycolumn chromatography on silica gel using methylene chloride/acetone(20:1) as eluent. The title compound was obtained (110 mg, 27%) as brownoil.

Intermediate 17. 4,4-Difluoro-6-(4-phenylbutoxy)hexanal

Intermediate 16 (110 mg, 0.39 mmol) was dissolved in a mixture of THF (3mL) and water (1 mL). To this solution was added sodium metaperiodate(272 mg, 1.27 mmol) and osmium tetroxide (4% water solution, 0.15 ml).The suspension was stirred 12 hours at room temperature, filtered andconcentrated. The residue was purified by column chromatography onsilica gel using methylene chloride/acetone (10:1) as eluent, to affordthe title compound (89 mg, 81%) as oil.

¹H-NMR (300 MHz, CDCl₃): 1.50-1.75 (m, 4H); 2.00-2.30 (m, 4H); 2.55-2.70(m, 4H); 3.40 (t, J=6.0 Hz, 2H); 3.55 (t, J=9.0 Hz, 2H); 7.15-7.20 (m,3H); 7.20-7.35 (m, 2H); 9.80 (bs, 1H).

Intermediate 18.(R,S)-2-{[4,4-Difluoro-6-(4-phenylbutoxy)hexyl]amino}-1-(2,2-dimethyl-4H-1,3-benzodioxin-8-yl)ethanol

To a solution of intermediate 17 (60 mg, 0.28 mmol) in MeOH (5 mL) wasadded acetic acid (0.1 molecular sieves (150 mg) and(R,S)-2-amino-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)ethanol (125 mg,0.56 mmol). The mixture was stirred 12 hours at room temperature, thensodium cyanoborohydride (21 mg, 0.33 mmol) was added, and the mixturewas further stirred for 1 hour. The mixture was filtered andconcentrated. The residue was dissolved in methylene chloride (10 mL)and washed with brine (3×2 mL), water (2×2 mL), dried (Na₂SO₄), andconcentrated. The residue (200 mg) was used without further purificationin the next step.

MS (M+): 491

Example 3(R,S)-4-(2-{[4,4-Difluoro-6-(4-phenylbutoxy)hexyl]amino}-1-hydroxy-ethyl)-2-(hydroxymethyl)phenol

Obtained from Intermediate 18 (0.20 g, 0.4 mmol) by the proceduredescribed in Example 1. Purification by column chromatography withsilica gel, eluting with methylene chloride/methanol/ammonium hydroxide(80:15:1.5) gave(R,S)-4-(2-{[4,4-difluoro-6-(4-phenylbutoxy)hexyl]amino}-1-hydroxy-ethyl)-2-(hydroxymethyl)phenol(69 mg, 38%) as oil.

¹H-NMR (400 MHz, dimethylsulfoxide-D6), 1.26-1.31 (m, 4H); 1.35-1.41 (m,2H); 1.46-1.55 (m, 2H); 2.12-2.25 (m, 2H); 2.54-2.58 (m, 4H); 2.71-2.75(m, 2H); 3.47 (d, J=6.4 Hz, 2H); 3.65 (t, J_(F-H)=13.5 Hz, 2H);4.45-4.50 (m, 4H); 4.91 (bs, 1H); 5.00 (bs, 1H); 6.7 (d, J=8.3 Hz, 1H);6.97 (dd, J₁=7.9 Hz, J₂=1.7 Hz, 1H); 7.19-7.31 (m, 6H); 9.17 (bs, 1H).

MS (M+): 452.

Intermediate 19. Difluoro(phenyl)acetaldehyde

Obtained from Intermediate 6 (1.0 g, 6.3 mmol) by the proceduredescribed for the Intermediate 13. The title compound was obtained (0.88g, 86%) as oil.

Intermediate 20. Ethyl (2E)-4,4-difluoro-4-phenylbut-2-enoate

Intermediate 19 (0.88 g, 5.64 mmol) was dissolved in THF (12 mL) and(carbethoxymethylene)triphenylphosphorane (1.96 g, 5.64 mmol) was thenadded. The solution was stirred at 50° C. for 12 hours. The mixture wasconcentrated and the residue was purified by column chromatography onsilica gel using n-hexane/AcOEt (5:1) as eluent. The title compound wasobtained (1.10 g, 89%) as pale yellow oil.

¹H-NMR (300 MHz, CDCl₃): 1.45 (t, J=7.1 Hz, 3H); 4.45 (q, J=7.1 Hz, 2H);6.45 (d, J_(F-H)=18 Hz, 1H); 7.15-7.30 (m, 1H); 7.60-7.70 (m, 3H);7.70-7.75 (m, 2H).

Intermediate 21, Ethyl 4,4-difluoro-4-phenylbutanoate

A solution of Intermediate 20 (1 g, 4.42 mmol) in methanol (20 mL) washydrogenated in the presence of palladium on charcoal (10 mg, 10%) for 3hours. The mixture was then filtered over Celite and the solvent removedunder reduced pressure. The residue (0.91 g) was used in the next stepwithout further purification.

Intermediate 22. 4,4-Difluoro-4-phenylbutan-1-ol

Obtained from intermediate 21 (0.9 g, 4.1 mmol) by the proceduredescribed in Intermediate 2. The title compound was obtained as oil(0.65 g, 85%).

¹H-NMR (300 MHz, CDCl₃): 1.50-1.75 (m, 2H); 2.10-2.30 (m, 2H); 3.55-3.65(m, 2H); 7.15-7.45 (m, 5H).

Intermediate 23. {4-[(6-Bromohexyl)oxy]-1,1-difluorobutyl}benzene

Obtained from Intermediate 22 (0.6 g, 3.22 mmol) by the proceduredescribed in Intermediate 3. The title compound was obtained (1.98 g,63% purity) as oil.

Intermediate 24.(R,S)-2-{[6-(4,4-Difluoro-4-phenylbutoxy)hexyl]amino}-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)ethanol

Obtained from Intermediate 23 (0.4 g, 0.6 mmol) by the proceduredescribed in Intermediate 4. The title compound was obtained (0.21 g,70%) as oil.

MS (M+): 491

Example 4(R,S)-4-(2-{[6-(4,4-Difluoro-4-phenylbutoxy)hexyl]amino}-1-hydroxy-ethyl)-2-(hydroxymethyl)phenol

Obtained from Intermediate 24 (0.2 g, 0.4 mmol) by the proceduredescribed in Example 1. The title compound was obtained (98 mg, 51%) asoil.

¹H-NMR (400 MHz, dimethylsulfoxide-D6); 1.25-1.31 (m, 4H); 1.34-1.41 (m,2H); 1.47-1.54 (m, 2H); 2.12-2.25 (m, 2H); 2.54-2.57 (m, 4H); 2.71-2.75(m, 2H); 3.47 (t, J=6.4 Hz, 2H); 3.66 (t, J_(F-H)=13.3 Hz, 2H);4.45-4.50 (m, 4H); 4.90-4.92 (m, 1H); 4.99 (bs, 1H); 6.68 (d, J=8.3 Hz,1H); 6.97 (dd, J₁=8.3 Hz, J₂2.1 Hz, 1H); 7.17-7.31 (m, 6H); 9.14 (bs,1H).

MS (M+): 451

Intermediate 25.(R,S)-8-(Benzyloxy)-5-(1-{[tert-butyl(dimethyl)silyl]oxy}-2-{[6-(2,2-difluoro-2-phenylethoxy)hexyl]amino}ethyl)quinolin-2(1H)-one

To a solution of(R,S)-8-(benzyloxy)-5-(2-bromo-1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)quinolin-2(1H)-one(1.58 g, 3.25 mmol) and Intermediate 9 (1.0 g, 3.9 mmol) indimethylsulfoxide (4.5 mL) was added sodium bicarbonate (0.82 g, 9.7mmol) and sodium iodide (0.73 m, 4.87 mmol). The mixture was heated at140° C. for 2 hours. After cooling, the reaction was diluted with water(20 mL) and extracted with diethyl ether (2×10 mL). The combined organicextracts were washed with water (2×5 mL) and brine (10 mL), dried(Na₂SO₄), and the solvent removed under reduced pressure. The titlecompound was obtained (2.14 g, 99%) as oil.

MS (M+): 664

Intermediate 26.(R,S)-8-(Benzyloxy)-5-(2-{[6-(2,2-difluoro-2-phenylethoxy)hexyl]-amino}-1-hydroxyethyl)quinolin-2(1H)-one

To a solution of Intermediate 25 (2.14 g, 3.21 mmol) in tetrahydrofuran(20 mL) was added tetra-n-butyl ammonium fluoride (1.68 g, 6.42 mmol).The mixture was stirred at room temperature overnight. The solvent wasremoved under reduced pressure. Purification by column chromatographyusing methylene chloride/methanol (from 95:5 to 85:15) as eluent gave(R,S)-8-(benzyloxy)-5-(2-{[6-(2,2-difluoro-2-phenylethoxy)hexyl]-amino}-1-hydroxyethyl)quinolin-2(1H)-one(1.27 g, 72%) as oil.

MS (m+): 550

Example 5(R,S)-5-(2-{[6-(2,2-Difluoro-2-phenylethoxy)hexyl]amino}-1-hydroxy-ethyl)-8-hydroxyquinolin-2(1H)-one

To a solution of Intermediate 26 (1.27 g, 2.3 mmol) in methanol (50 mL)was added 20% palladium on charcoal (300 mg). The mixture washydrogenated at 30 psi for 3 hours. The catalyst was filtered throughCelite and the solvent concentrated. The resulting oil was purified bycolumn chromatography with silica gel eluting with methylenechloride/ethanol/ammonium hydroxide (from 80:8:1 to 40:8:1) to give(R,S)-5-(2-{[6-(2,2-difluoro-2-phenylethoxy)hexyl]amino}-1-hydroxy-ethyl)-8-hydroxyquinolin-2(1H)-one(0.44 g, 41%) as oil.

¹H-NMR (400 MHz, dimethylsulfoxide-D6): 1.14-1.21 (m, 2H); 1.28-1.65 (m,6H); 2.61-2.72 (m, 2H); 3.14-3.18 (m, 2H); 3.90 (t, J_(F-H)=13.9 Hz,2H); 4.96 (dd, J₁=8.2 Hz, J₂=4.3 Hz, 1H); 6.55 (d, J=9.8 Hz, 1H); 6.80(d, J=8.2 Hz, 1H): 7.00 (d, J=8.2 Hz, 1H); 7.47-7.54 (m, 5H); 8.16 (d,J=9.8 Hz, 1H).

MS (M+): 496

Intermediate 27. Ethyl (3-methylphenyl)(oxo)acetate

A suspension of selenium dioxide (6.82 g, 61.4 mmol) in ethanol (60 mL)was refluxed for 10 minutes and then, 2-bromo-1-m-tolylethanone (13.1 g,61.4 mmol) was added. The mixture was refluxed overnight. The cooledreaction was filtered through Celite and the solvent removed underreduced pressure. The residue was diluted with methylene chloride (50mL), washed with water (2×25 mL), dried (Na₂SO₄), and concentrated.Purification by column chromatography with silica gel using methylenechloride as eluent gave the title compound (9.6 g, 81%) as oil.

¹H NMR (300 MHz, CDCl₃): 1.43 (t, J=7.1 Hz, 3H); 2.43 (s, 3H); 4.46 (q,J=7.1 Hz, 2H); 7.38-7.49 (m, 2H); 7.79-7.81 (d, J=6.6 Hz, 2H).

Intermediate 28. Ethyl difluoro(3-methylphenyl)acetate

Obtained from Intermediate 27 (9.6 g, 50 mmol) by the proceduredescribed in Intermediate 1. Ethyl difluoro(3-methylphenyl)acetate wasobtained (3.55 g, 80%) as oil.

¹H NMR (300 MHz, CDCl₃): 1.43 (t, J=7.1 Hz, 3H); 2.43 (s, 3H); 4.46 (q,J=7.1 Hz, 2H); 7.25-7.61 (m, 4H).

Intermediate 29. 2,2-Difluoro-2-(3-methylphenyl)ethanol

Obtained from Intermediate 28 (9.5 g, 40 mmol) by the proceduredescribed in Intermediate 2. The title compound was obtained (5.55 g,80%) as oil.

¹H NMR (300 MHz, CDCl₃): 2.43 (s, 3H); 4.00 (t, J_(F-H)=13.5 Hz, 2H);7.25-7.35 (m, 4H).

Intermediate 30.1-{2-[(6-Bromohexyl)oxy]-1,1-difluoroethyl}-3-methylbenzene

Obtained from Intermediate 29 (5.55 g, 32.2 mmol) by the proceduredescribed in Intermediate 3. Purification by column chromatography withsilica gel and n-hexane/ethyl acetate (from pure n-hexane to 10:1) aseluent gave the title compound (10.99 g, 100%) as oil.

¹H-NMR (300 MHz, CDCl₃):1.40-1.60 (m, 2H); 1.81-1.91 (m, 4H); 2.39 (s,3H); 3.36-3.43 (m, 4H); 3.53 (t, J=6.5 Hz, 2H); 3.82 (t, J_(F-H)=13.2Hz, 2H); 7.24-7.26 (m, 1H); 7.31-7.32 (m, 3H)

Intermediate 31.2-{6-[2,2-Difluoro-2-(3-methylphenyl)ethoxy]hexyl}-1H-isoindole-1,3(2H)-dione

Obtained from intermediate 30 (8.77 g, 26.2 mmol) by the proceduredescribed in Intermediate 8. Purification by column chromatography withsilica gel and methylene chloride as eluent gave the title compound (4.0g, 40%) as oil,

¹H-NMR (300 MHz, CDCl₃): 1.28-1.33 (m, 4H); 1.51-1.56 (m, 2H); 1.62-1.66(m, 2H); 2.39 (s, 3H); 3.51 (t, J=6.5 Hz, 2H); 3.63-3.68 (m, 2H); 3.81(t, J_(F-H)=13.2 Hz, 2H); 7.30-7.31 (m, 4H); 7.70-7.73 (m, 2H);7.83-7.86 (m, 2H).

Intermediate 32. {6-[2,2-Difluoro-2-(3-methylphenyl)ethoxy]hexyl}amine

Obtained from Intermediate 31 (4.0 g, 14.4 mmol) by the proceduredescribed in intermediate 9.{6-[2,2-Difluoro-2-(3-methylphenyl)ethoxy]hexyl}amine was obtained (1.93g, 50%) as oil.

¹H-NMR (300 MHz, CDCl₃): 1.29-1.32 (m, 4H); 1.37-1.44 (m, 2H); 1.52-1.58(m, 2H); 2.39 (s, 3H); 2.66 (t, J=6.9 Hz, 2H); 3.53 (t, J=6.5 Hz, 2H);3.83 (t, J_(F-H)=13.2 Hz, 2H): 7.30-7.32 (m, 4H).

MS (M+): 271

Intermediate 33.(R,S)-1-[4-(Benzyloxy)-3-(hydroxymethyl)phenyl]-2-({6-[2,2-difluoro-2-(3-methylphenyl)ethoxy]hexyl}amino)ethanol

Obtained from Intermediate 32 (0.50 g, 1.85 mmol) by the proceduredescribed in Intermediate 10.(R,S)-1-[4-(Benzyloxy)-3-(hydroxymethyl)phenyl]-2-({6-[2,2-difluoro-2-(3-methylphenyl)ethoxy]hexyl}amino)ethanolwas obtained (0.98 g, 100%) as oil.

¹H-NMR (300 MHz, CDCl₃): 1.31-1.33 (m, 4H); 1.43-1.56 (m, 5H); 2.39 (s,3H); 2.61-2.67 (m, 3H); 2.83-2.88 (m, 1H); 3.53 (t, J=6.5 Hz, 2H); 3.82(t, J_(F-H)=13.3 Hz, 2H); 4.62-4.66 (m, 1H); 4.74 (s, 2H); 5.12 (s, 2H);6.92 (d, J=8.2 Hz, 1H); 7.31-7.43 (m, 11H).

Example 6(R,S)-4-[2-({6-[2,2-Difluoro-2-(3-methylphenyl)ethoxy]hexyl}amino)-1-hydroxyethyl]-2-(hydroxymethyl)phenol

Obtained from Intermediate 33 (0.98 g, 1.85 mmol) by the proceduredescribed in Example 2. Purification by column chromatography withsilica gel, using with methylene chloride/ethanol/ammonium hydroxide(40:8:1) as eluent gave(R,S)-4-[2-({6-[2,2-difluoro-2-(3-methylphenyl)ethoxy]hexyl}amino)-1-hydroxyethyl]-2-(hydroxymethyl)phenol(0.44 g, 55%) as oil.

¹H-NMR (300 MHz, Cl₃CD), 1.25-1.33 (m, 4H); 1.43-1.56 (m, 4H); 2.39 (s,3H); 2.58-2.70 (m, 4H); 2.76-2.82 (m, 2H); 2.98 (m, 4H); 3.52 (t, J=6.5Hz, 2H); 3.82 (t, J_(F-H)=13.5 Hz, 2H); 4.57-4.60 (d, J=8.0 Hz, 1H);4.77 (s, 2H); 6.81 (d, J=9.1 Hz, 2H); 7.0 (s, 1H); 7.12 (d, J=9.1 Hz,1H); 7.26-7.27 (m, 1H); 7.30-7.32 (m, 3H).

MS (M+): 437.

Intermediate 34.(R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-one

To a solution of(R)-2-amino-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)ethanol (2.53 g,11.3 mmol) in chloroform (12 mL) was added carbonyldiimidazol (2.75 g,17 mmol) and triethylamine (2.37 mL, 17 mmol). The mixture was stirredat room temperature overnight. The solvent was removed under reducedpressure and the residue diluted with ethyl acetate (25 mL). The organiclayer was washed with water (2×10 mL), brine (10 mL), dried (Na₂SO₄),and the solvent reduced under reduced pressure. Purification by columnchromatography with silica gel and n-hexane/ethyl acetate (1:2) aseluent yielded the title compound (1.63 g, 51%).

1H NMR (300 MHz, CDCl₃): 1.55 (s, 6H); 3.54 (t, J=8.1 Hz, 1H); 3.94 (t,J=8.7 Hz, 1H); 4.86 (s, 2H); 5.10 (bs, 1H); 5.56 (t, J=8.1 Hz, 1H); 6.85(d, J=8.5 Hz, 1H); 7.04-7.07 (m, 1H); 7.15-7.18 (m, 1H).

Intermediate 35.(R)-3-[6-(2,2-Difluoro-2-phenylethoxy)hexyl]-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-one

To a cooled suspension of 60% sodium hydride (0.37 g, 9.27 mmol) indimethylformamide (7.5 mL) was added a solution of intermediate 34 (1.65g, 6.62 mmol) in dimethylformamide (15 mL). The mixture was stirred at0° C. for 1 hour. Then, a solution of intermediate 7 (3.19 g, 9.93 mmol)in dimethylformamide (9 mL) was added at the same temperature. Themixture was heated to room temperature and stirred for 2 hours, Thecrude reaction was cooled to 0° C. and then 2N HCl (1.5 mL) and water(20 mL) were added. The solution was extracted with ethyl ether (2×20mL). The organic layer was washed with water (2×10 mL), dried (Na₂SO₄),and the solvent removed under reduced pressure. Purification by columnchromatography with silica gel eluting with n-hexane/ethyl acetate (1:1)gave(R)-3-[6-(2,2-difluoro-2-phenylethoxy)hexyl]-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-one(1.5 g, 46%) as oil.

¹H NMR (300 MHz, CDCl₃): 1.26-1.53 (m, 6H); 1.55 (s, 6H); 3.18-3.44 (m,5H); 3.52 (t, J=6.3 Hz, 1H); 3.79-3.9 (m, 3H); 4.12 (q, J=7.1 Hz, 1H);4.84 (s, 2H); 5.37-5.44 (m, 1H); 6.84 (d, J=8.5 Hz, 1H); 7.00 (s, 1H);7.12 (d, J=8.5 Hz, 1H); 7.41-7.46 (m, 3H); 7.50-7.53 (m, 2H).

Intermediate 36.(1R)-2-{[6-(2,2-Difluoro-2-phenylethoxy)hexyl]amino}-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)ethanol

To a solution of Intermediate 35 (1.5 g, 3.0 mmol) in tetrahydrofuran(60 mL) was added potassium trimethylsilanolate (1.54 g, 12 mmol). Themixture was stirred at 70° C. under inert atmosphere for 2 hours. To thecooled reaction mixture was added saturated solution of ammoniumchloride (60 mL). The suspension was extracted with methylene chloride(2×30 mL). The organic layer was washed with water (2×25 mL) and brine(25 mL), dried (Na₂SO₄) and the solvent removed under reduced pressure.The residue was purified by column chromatography with silica gel andmethylene chloride/ethanol/ammonium hydroxide (100:8:1) as eluent. Thetitle compound was obtained (900 mg, 65%) as oil.

¹H NMR (300 MHz, CDCl₃): 1.2-1.32 (m, 6H): 1.53 (s, 6H); 2.58-2.69 (m,5H); 2.83-2.88 (m, 1H); 3.52 (t, J=6.5 Hz, 2H); 3.84 (t, J_(F-H)=13.2Hz, 1H); 4.09-4.13 (m, 1H); 4.58-4.61 (m, 1H); 4.84 (s, 2H); 6.78 (d,J=8.5 Hz, 1H); 7.01 (s, 1H); 7.12 (d, J=8.5 Hz, 1H); 7.42-7.44 (m,J₁=4.9 Hz, J₂=2.2 Hz, 3H); 7.50-7.51 (m, J=3.3 Hz, 2H)

Example 74-((1R)-2-{[6-(2,2-Difluoro-2-phenylethoxy)hexyl]amino}-1-hydroxyethyl)-2-(hydroxymethyl)phenol

Obtained from Intermediate 35 (0.90 g, 1.94 mmol) by the proceduredescribed in Example 1. Purification by column chromatography withsilica gel and methylene chloride/ethanol/ammonium hydroxide (40:8:1) aseluent gave4-((1R)-2-{[6-(2,2-difluoro-2-phenylethoxy)hexyl]amino}-1-hydroxyethyl)-2-(hydroxymethyl)phenol(0.44 g, 55%) as oil.

¹H-NMR (300 MHz, Cl₃CD), 1.27-1.31 (m, 4H); 1.41-1.57 (m, 4H); 2.18 (bs,2H); 2.55, 2.68 (m, 4H); 2.77-2.82 (m, 1H); 3.50 (s, 1H); 3.52 (t, J=6.3Hz, 2H); 3.84 (t, J_(F-H)=13.3 Hz, 2H); 4.58 (dd, J₁=9.2 Hz, J₂=3.4 Hz,1H); 4.83 (d, 2H); 6.84 (d, J=8.2 Hz, 1H); 7.02 (d, J=2.0 Hz, 1H); 7.16(dd, J₁=8.4 Hz, J₂=2.1 Hz, 1H); 7.42-7.44 (m, 3H); 7.50-7.54 (m, 2H),

MS (M+): 423.

Intermediate 37.2,2,3,3-Tetrafluoro-4-{[(2E)-3-phenylprop-2-en-1-yl]oxy}butan-1-ol

To a solution 2,2,3,3-tetrafluoro-1,4-butanediol (2.0 g, 12.3 mmol) indimethylformamide (30 mL) was added 60% sodium hydride (0.140 g, 18.4mmol). The mixture was stirred at room temperature for 1.30 hours. Then,a solution of cinnamyl bromide (3.2 g, 12.3 mmol) in dimethylformamide(40 mL) was added. The mixture was stirred at room temperature overnightand concentrated. The residue was dissolved with ethyl acetate (50 mL),washed with water (2×25 mL) and brine (25 mL), dried (Na₂SO₄), and thesolvent removed under reduced pressure. Purification by columnchromatography with silica gel and n-hexane/ethyl acetate (from puren-hexane to 5:1) gave the title compound (1.8 g, 54%) as oil.

¹H NMR (300 MHz, CDCl₃): 2.78-3.18 (bs, 1H); 3.80-4.05 (m, 4H); 4.28 (d,J=9 Hz, 2H); 6.18-6.32 (m, 1H); 6.58-6.62 (m, 1H); 7.20-7.35 (m, 5H).

Intermediate 38.2,2,3,3-Tetrafluoro-4-{[(2E)-3-phenylprop-2-en-1-yl]oxy}butanal

Obtained from intermediate 37 (1.80 g, 6.47 mmol) by the proceduredescribed in Intermediate 13.2,2,3,3-Tetrafluoro-4-{[(2E)-3-phenylprop-2-en-1-yl]oxy}butanal wasobtained (1.37 g, 77%) as oil.

¹H NMR (300 MHz, CDCl₃): 3.80-4.05 (m, 4H); 4.20-4.40 (m, 2H); 6.18-6.32(m, 1H); 6.58-6.62 (t, J_(F-H)=18 Hz, 1H); 7.20-7.35 (m, 5H); 9.50 (bs,1H).

Intermediate 39. Ethyl(2E)-4,4,5,5-tetrafluoro-6-{[(2E)-3-phenylprop-2-en-1-yl]oxy}-hex-2-enoate

Obtained from Intermediate 38 (1.37 g, 4.96 mmol) by the proceduredescribed in Intermediate 20. Purification by column chromatography withsilica gel using n-hexane/ethyl acetate (15:1) as eluent gave the titlecompound (1.2 g, 70%) as oil.

¹H NMR (300 MHz, CDCl₃): 1.20-1.35 (m, 3H); 3.80-4.05 (m, 2H); 4.20-4.40(m, 4H); 5.90-6.10 (q, J_(F-H)=13.5 Hz, 1H); 6.20-6.38 (m, 2H);6.60-6.70 (m, 1H); 7.21-7.31 (m, 5H).

Intermediate 40. Ethyl 4,4,5,5-tetrafluoro-6-(3-phenylpropoxy)hexanoate

Obtained from Intermediate 39 (1.2 g, 3.46 mmol) by the proceduredescribed in intermediate 21. Ethyl4,4,5,5-tetrafluoro-6-(3-phenylpropoxy)hexanoate was obtained (1.0 g,82%) as oil.

¹H NMR (300 MHz, CDCl₃): 1.22 (t, J=9 Hz, 3H); 1.83-1.95 (m, 2H)2.30-2.55 (m, 2H); 2.70-2.63 (m, 2H); 2.85-2.80 (m, 2H); 3.50-3.60 (m,2H); 3.80-3.95 (q, J_(F-H)=18.0 Hz, 2H); 4.10-4.20 (m, 2H);7.15-7.25 (m,3H); 7.25-7.41 (m, 2H).

Intermediate 41. 4,4,5,5-Tetrafluoro-6-(3-phenylpropoxy)hexan-1-ol

Obtained from Intermediate 40 (1.0 g, 2.85 mmol) by the proceduredescribed in Intermediate 2. Purification by column chromatography withsilica gel and n-hexane/ethyl acetate (from 10:1 to 5:1) as eluent gavethe title compound (0.68 g, 82%) as oil,

¹H NMR (300 MHz, CDCl₃): 1.70-2.01 (m, 4H); 2.05-2.15 (m, 2H); 2.65-2.75(m, 2H); 3.50-3.60 (m, 2H); 3.62-3.75 (m, 2H); 3.78-3.95 (t,J_(F-H)=18.0 Hz, 2H); 7.05-7.20 (m, 3H); 7.20-7.35 (m, 2H).

Intermediate 42. 4,4,5,5-Tetrafluoro-6-(3-phenylpropoxy)hexanal

Obtained from intermediate 41 (0.68 g, 2.20 mmol) by the proceduredescribed in Intermediate 13.4,4,5,5-Tetrafluoro-6-(3-phenylpropoxy)hexanal was obtained (0.32 g,47%) as oil.

¹H NMR (300 MHz, CDCl₃): 1.80-2.00 (m, 2H); 2.25-2.55 (m, 2H); 2.65-2.85(m, 4H); 3.50-3.65 (m, 2H); 3.75-3.95 (t, J_(F-H)=18.0 Hz, 2H);7.05-7.20 (m, 3H); 7.20-7.35 (m, 2H); 9.80 (bs, 1H).

Intermediate 43.(R,S)-1-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-{[4,4,5,5-tetrafluoro-6-(3-phenylpropoxy)hexyl]amino}ethanol

Obtained from intermediate 42 (0.32 g, 1.05 mmol) by the proceduredescribed in Intermediate 18. Purification by column chromatography withsilica gel and methylene chloride/triethylamine (100:1) as eluent gavethe title compound (0.17 g, 32%) as oil.

MS (M+): 513

Example 8(R,S)-2-(Hydroxymethyl)-4-(1-hydroxy-2-{[4,4,5,5-tetrafluoro-6-(3-phenylpropoxy)hexyl]amino}ethyl)phenol

Obtained from Intermediate 43 (0.17 g, 0.33 mmol) by the proceduredescribed in Example 1. Purification by column chromatography withsilica gel and methylene chloride/methanol/ammonium hydroxide (40:4:0.2)as eluent gave(R,S)-2-(hydroxymethyl)-4-(1-hydroxy-2-{[4,4,5,5-tetrafluoro-6-(3-phenylpropoxy)hexyl]amino}ethyl)phenol(0.15 g, 96%) as oil.

¹H-NMR (400 MHz, dimethylsulfoxide-D6): 1.57-1.64 (m, 2H); 1.78-1.86 (m,2H); 2.05-2.17 (m, 2H); 2.56-2.63 (m, 4H); 3.54 (d, J=6.4 Hz, 2H); 3.91(d, J_(F-H)=14.9 Hz, 3H); 4.45-4.51 (m, 3H); 4.91 (t, J=5.6 Hz, 1H);5.01 (d, J=3.7 Hz, 1H); 6.68 (d, J=7.9 Hz, 1H); 6.97 (dd, J₁=8.3 Hz,J₂=2.1 Hz, 1H); 7.15-7.20 (m, 3H); 7.25-7.30 (m, 3H); 9.15 (bs, 1H),

MS (M+): 473

Intermediate 44. N-Benzyl-6-(2,2-difluoro-2-phenylethoxy)hexan-1-amine

A solution of Intermediate 7 (5.0 g, 15.6 mmol) and benzyl amine (3.4mL, 31.1 mmol) was heated at 120° C. for two hours. The crude reactionwas treated with ethyl ether and the resulting solid was filtered. Thesolvent was concentrated and the resulting oil was purified by columnchromatography with silica gel and methylene chloride/methanol (from99:1 to 95:5) as eluent, to yieldN-benzyl-6-(2,2-difluoro-2-phenylethoxy)hexan-1-amine (3.2 g, 59%) asoil.

¹H NMR (300 MHz, CDCl₃): 1.24-1.32 (m, 2H); 1.46-1.63 (m, 4H); 2.58-2.64(m, 4H); 3.49-3.53 (t, J=6.5 Hz, 2H); 3.79-3.88 (m, 4H); 7.30-7.33 (m,5H); 7.42-7.44 (m, 3H); 7.50-7.54 (m, 2H).

Intermediate 45.(R,S)-2-{Benzyl[6-(2,2-difluoro-2-phenylethoxy)hexyl]amino}-1-[4-(benzyloxy)-3-nitrophenyl]ethanol

A solution of Intermediate 44 (3.2 g, 9.22 mmol) and2-(3-nitro-4-phenoxyphenyl)-oxirane (2.27 g, 8.38 mmol) was heated at120° C. for 2 hours. An HPLC-MS analysis of the crude reaction revealedthat there were two main products:(R,S)-2-{benzyl[6-(2,2-difluoro-2-phenylethoxy)hexyl]amino}-1-[4-(benzyloxy)-3-nitrophenyl]ethanoland the corresponding isomer(R,S)-1-{benzyl[6-(2,2-difluoro-2-phenylethoxy)hexyl]amino}-1-[4-(benzyloxy)-3-nitrophenyl]ethanol(60:40). The reaction was cooled and the resulting oil (5.18 g) was usedin the next step without further purification.

Intermediate 46.(R,S)-1-[3-Amino-4-(benzyloxy)phenyl]-2-{benzyl[6-(2,2-difluoro-2-phenylethoxy)hexyl]amino}ethanol

To a solution of Intermediate 45 (5.18 g, 8.38 mmol) in ethanol (110 mL)was added tin dichloride (6.34 g, 33.5 mmol). The mixture was refluxedfor 2 hours. The reaction was cooled and the solvent was removed underreduced pressure. The resulting oil (3.92 g) was used in the next stepwithout further purification.

Example 9(R,S)-[5-(2-{[6-(2,2-Difluoro-2-phenylethoxy)hexyl]amino}-1-hydroxy-ethyl)-2-hydroxyphenyl]formamide

A mixture of formic acid (0.62 mL, 13.32 mmol) and acetic anhydride(0.78 g, 7.65 mmol) were heated at 50° C. for 15 minutes. The mixturewas cooled to 10° C. and a solution of intermediate 46 (3.2 g) intetrahydrofuran (18 mL) and toluene (18 mL) was added dropwise. Themixture was stirred at room temperature for 20 minutes. The solvent wasremoved under reduced pressure. The resulting oil was purified by columnchromatography with silica gel and methylene chloride/methanol (from98:2 to 95:5) as eluent to give crude dibenzylated(R,S)-[5-(2-{[6-(2,2-difluoro-2-phenylethoxy)hexyl]-amino}-1-hydroxy-ethyl)-2-hydroxyphenyl]formamide(2.44 g) as oil. A solution of this oil in ethanol (150 mL) washydrogenated in the presence of palladium on charcoal (0.3 g) for 4hours. The mixture was then filtered over Celite and the solvent removedunder reduced pressure. The residue was purified by columnchromatography with silica gel and methylene chloride/ethanol/ammoniumhydroxide (80:8:1) as eluent to give(R,S)-[5-(2-{[6-(2,2-difluoro-2-phenylethoxy)hexyl]amino}-1-hydroxy-ethyl)-2-hydroxyphenyl]formamide(464 mg, 14% three step overall yield) as oil.

¹H-NMR (400 MHz, dimethylsulfoxide-D6): 1.17-1.18 (m, 4H); 1.26-1.33 (m,2H); 1.36-1.44 (m, 2H); 2.44-2.47 (m, 2H); 2.50-2.57 (m, 2H); 3.41-3.45(d, J=6.5 Hz, 2H); 3.90 (d, J=13.7 Hz, 2H); 4.42-4.48 (m, 1H); 6.77 (d,J=8.2 Hz, 1H); 6.85 (dd, J₁=8.2 Hz, J₂=2.0 Hz, 1H); 7.45-7.53 (m, 5H);7.99 (d, J=2.0 Hz, 1H); 8.24 (s, 1H); 9.51 (bs, 1H).

MS (M+): 436

Intermediate 47. Ethyl (3-bromophenyl)(oxo)acetate

Obtained from 2-bromo-1-m-bromophenylethanone (27.7 g, 0.10 mol) by theprocedure described in Intermediate 27. Purification by columnchromatography with silica gel using methylene chloride as eluent gavethe title compound (20.7 g, 81%) as oil.

¹H-NMR (300 MHz, CDCl₃): 1.40 (t, J=7.1 Hz, 3H); 4.45 (q, J=7.1 Hz, 2H);7.40 (t, J=9.0 Hz, 1H); 7.80 (d, J=9.0 Hz, 1H); 7.98 (d, J=9.0 Hz, 1H);8.20 (s, 1H).

Intermediate 48. Ethyl(3-bromophenyl)difluoroacetate

Obtained from intermediate 47 (28.80 g, 0.112 mol) by the proceduredescribed in Intermediate 1. Purification by column chromatography withsilica gel and n-hexane/ethyl acetate (4:1) as eluent gave the titlecompound (26.3 g, 84%) as oil.

¹H-NMR (300 MHz, CDCl₃): 1.30 (t, J=7.1 Hz, 3H); 4.30 (q, J=7.1 Hz, 2H);7.30 (t, J=9.0 Hz, 1H); 7.55 (d, J=9.0 Hz, 1H); 7.65 (d, J=9.0 Hz, 1H);7.78 (s, 1H).

Intermediate 49. 2-(3-Bromopheny)-2,2-difluoroethanol

Obtained from Intermediate 48 (21.1 g, 75.8 mmol) by the proceduredescribed in Intermediate 2. The title compound was obtained (17.2 g,96%) as oil.

¹H-NMR (300 MHz, CDCl₃): 3.95 (t, J_(F-H)=13.5 Hz, 2H); 7.30 (t, J=9.0Hz, 1H); 7.55 (d, J=9.0 Hz, 1H); 7.65 (d, J=9.0 Hz, 1H); 7.70 (s, 1H).

Intermediate 50.1-Bromo-3-{2-[(6-bromohexyl)oxy]-1,1-difluoroethyl}benzene

Obtained from Intermediate 49 (17.6 g, 74 mmol) by the proceduredescribed in Intermediate 3. The crude oil was purified by distillationto yield the title compound as oil of 60% of purity (9.5 g). Thedistillation residue was purified by column chromatography with silicagel and methylene chloride as eluent to yield a second batch of1-bromo-3-{2-[(6-bromohexyl)oxy]-1,1-difluoroethyl}benzene of 65% ofpurity (15.2 g) (overall yield: 53%).

¹H NMR (300 MHz, CDCl₃): 1.25-1.55 (m, 8H); 1.81-1.88 (m, 1H); 3.37-3.41(m, 1H); 3.46-3.53 (m, 2H); 3.78-3.86 (m, 2H); 7.30-7.34 (m, 1H);7.44-7.46 (m, 1H); 7.58 (d, J=8.0 Hz, 1H); 7.67 (s, 1H).

Intermediate 51.(R,S)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-one

To a solution of(R,S)-2-amino-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)ethanol (5.0 g,22.3 mmol) in methylene chloride (100 mL) was added ditertbutyldicarbonate (5.35 g, 24.5 mmol) and triethylamine (3.4 mL, 24.5 mmol).The mixture was stirred at room temperature for 2 hours. The organiclayer was washed with water (2×10 mL), brine (10 mL), dried (Na₂SO₄),and the solvent reduced under reduced pressure. Trituration with ethylether gave the protected starting amine (6.8 g, 94%) as an off-whitesolid. A solution of this solid in dimethylformamide (30 mL) was addeddropwise to a cooled suspension of sodium hydride (1.07 g, 27 mmol) indimethylformamide (30 mL). The mixture was allowed to reach roomtemperature and then was stirred at 40° C. overnight. The solvent wasremoved under reduced pressure. The residue was diluted with ethylacetate (60 mL) and the organic layer was acidified with 2N HCl, washedwith water (2×30 mL), brine (2×30 mL), dried (Na₂SO₄), and the solventreduced under reduced pressure. The title compound was obtained (4.4 g,85%) as oil.

¹H NMR (300 MHz, CDCl₃): 1.52-1.61 (m, 6H); 3.55 (t, J=8.2 Hz, 1H); 3.94(t, J=8.7 Hz, 1H); 4.86 (s, 2H); 5.42 (bs, 1H); 5.55 (t, J=8.1 Hz, 1H);6.85 (d, J=8.5 Hz, 1H); 7.04 (d, J=1.6 Hz, 1H); 7.17 (dd, J₁=8.4 Hz,J₂=2.3 Hz, 1H)

Intermediate 52.(R,S)-3-{6-[2-(3-Bromophenyl)-2,2-difluoroethoxy]hexyl}-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-one

Obtained from Intermediate 50 (4.6 g of 50% purity, 5.7 mmol) andintermediate 51 (1.14 g, 4.56 mmol) by the procedure described inIntermediate 35. Purification by column chromatography with silica geland methylene chloride/methanol (from pure methylene chloride to 98:2)as eluent gave the title compound (2.06 g, 80%) as oil.

¹H NMR (300 MHz, CDCl₃): 1.30-1.32 (m, 4H); 1.52-1.58 (m, 3H); 1.54 (s,6H); 3.18-3.43 (m, 4H); 3.48-3.54 (m, 2H); 3.77-3.88 (m, 3H); 4.84 (s,2H); 5.40 (t, J=8.0 Hz, 1H); 6.84 (d, J=8.5 Hz, 1H); 7.00 (d, J=1.6 Hz,1H); 7.12 (dd, J₁=8.4 Hz, J₂2.3 Hz, 1H); 7.31-7.34 (m, 1H); 7.44-7.46(m, 1H); 7.56-7.59 (d, J=8.0 Hz, 1H); 7.67 (s, 1H).

Intermediate 53.(R,S)-2-({6-[2-(3-bromophenyl)-2,2-difluoroethoxy]hexyl}amino)-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)ethanol

Obtained from intermediate 52 (1.24 g, 2.18 mmol) by the proceduredescribed in Intermediate 36. Purification by column chromatography withsilica gel and methylene chloride/methanol/ammonium hydroxide (100:8:1)as eluent gave the title compound (0.9 g, 76%) as oil.

1H NMR (300 MHz, CDCl₃): 1.23-1.32 (m, 6H); 1.54 (s, 6H); 2.58-2.70 (m,3H); 2.84-2.89 (m, 1H); 3.49-3.53 (m, 2H); 3.69-3.86 (m, 4H); 4.59-4.64(dd, J₁=9.2 Hz, J₂=3.4 Hz, 1H); 4.85 (s, 2H); 6.79 (d, J=8.5 Hz, 1H);7.01 (s, 1H); 7.11-7.14 (m, 1H); 7.32 (d, J=7.7 Hz, 1H); 7.44-7.47 (m,1H); 7.58 (d, J=8.0 Hz, 1H); 7.67 (s, 1H).

Example 10(R,S)-4-[2-({6-[2-(3-Bromophenyl)-2,2-difluoroethoxy]hexyl}amino)-1-hydroxyethyl]-2-(hydroxymethyl)phenol

Obtained from Intermediate 53 (0.90 g, 1.66 mmol) by the proceduredescribed in Example 1. Purification by column chromatography withsilica gel, using methylene chloride/ethanol/ammonium hydroxide (40:8:1)as eluent gave(R,S)-4-[2-({6-[2-(3-bromophenyl)-2,2-difluoroethoxy]hexyl}amino)-1-hydroxyethyl]-2-(hydroxymethyl)phenol(0.36 g, 55%) as an off-white solid.

¹H-NMR (300 MHz. Cl₃CD): 1.27-1.30 (m, 4H); 1.41-1.56 (m, 4H); 2.51-2.77(m, 4H); 3.51 (t, J=6.3 Hz, 2H); 3.53 (bs, 4H); 3.82 (t, J_(F-H)=12.8Hz, 2H); 4.53-4.57 (m, 1H); 4.76 (s, 2H); 6.80 (d, J=8.2 Hz, 1H); 6.96(d, J=1.9 Hz, 1H); 7.11 (dd, J₁=8.0, J₂=1.9 Hz, 1H); 7.32 (d, J=8.0 Hz,1H); 7.44-7.47 (m, 1H); 7.56-7.59 (m, 1H); 7.67 (s, 1H).

MS (M+): 502.

Intermediate 54.(R,S)-3-{6-[2-(3-Aminophenyl)-2,2-difluoroethoxy]hexyl}-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-one

To a solution of Intermediate 52 (4.65 g, 8.18 mmol) in toluene (20 mL)was added bis(dibenzylideneacetone)palladium (230 mg, 0.4 mmol),tri-tert-butylphosphine (83 □L, 0.4 mmol) and lithiumbis(trimethylsilyl)amide, 1M solution in hexane (9 mL, 9 mmol) underinert atmosphere. The mixture was stirred at room temperature overnight.The reaction was diluted with ethyl ether (20 mL) and 2N HCl was added(0.25 mL). The organic layer was washed with 2N sodium hydroxide (2×20mL), water (20 mL) and brine (20 mL), dried (Na₂SO₄); and the solventremoved under reduced pressure. Purification by column chromatographywith silica gel and methylene chloride/methanol (from pure methylenechloride to 98:2) as eluent gave the title compound (2.71 g, 66%) asoil.

1H NMR (300 MHz, CDCl₃): 1.30-1.38 (m, 4H); 1.48-1.58 (m, 3H); 1.55 (s,6H); 3.23-3.43 (m, 3H); 3.52 (t, J=6.3 Hz, 2H); 3.76-3.89 (m, 4H); 4.85(s, 2H); 5.40 (t, J=8.0 Hz, 1H); 6.72-6.76 (m, 1H); 6.82-6.89 (m, 3H);7.01 (d, J=1.1 Hz, 1H); 7.11-7.22 (m, 2H).

Intermediate 55.(R,S)—N-{3-[2-((6-[5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]hexyl}oxy)-1,1-difluoroethyl]phenyl}urea

To a solution of Intermediate 54 (2.71 g, 5.4 mmol) in acetic acid (20ml) and water (10 ml) was added a solution of potassium cyanide (0.87 g,10.7 mmol) in water (20 mL). The mixture was stirred overnight underinert atmosphere. The crude reaction was diluted with water andextracted with ethyl acetate (3×15 mL). The combined organic extractswere washed with water (2×15 mL) and brine (20 mL), dried (Na₂SO₄), andconcentrated. Purification by column chromatography with silica gel andethyl acetate as eluent gave the title compound (2.2 g, 73%) as oil.

¹H NMR (300 MHz, CDCl₃): 1.30-1.38 (m, 4H); 1.47-1.58 (m, 3H); 1.55 (s,6H); 3.25-3.41 (m, 3H); 3.45-3.51 (m, 2H); 3.79-3.93 (m, 4H); 4.85 (s,2H); 5.15 (bs, 2H); 5.46 (t, J=8.2 Hz, 1H); 6.87 (d, J=8.5 Hz, 1H); 7.00(d, J=1.9 Hz, 1H); 7.12-7.16 (m, 2H); 7.30-7.38 (m, 2H): 7.88-7.90 (m,1H); 8.00 (bs, 1H).

Intermediate 56.(R,S)—N-(3-{2-[(6-{[2-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]amino}hexyl)oxy]-1,1-difluoroethyl}phenyl)urea

Obtained from Intermediate 55 (2.2 g, 4 mmol) by the procedure describedin Intermediate 36. Purification by column chromatography with silicagel and methylene chloride/ethanol/ammonium hydroxide (100:8:1) aseluent gave the title compound (1.12 g, 54%) as oil.

1H NMR (300 MHz, CDCl₃): 1.22-1.28 (m, 4H); 1.39-1.49 (m, 4H); 1.53 (s,6H); 2.56-2.87 (m, 3H); 3.48 (t, J=6.0 Hz, 2H); 3.69-3.86 (m, 4H): 4.68(dd, J₁=9.2 Hz, J₂=3.7 Hz, 1H); 4.82 (s, 2H); 4.95 (bs, 2H); 6.79 (d,J=8.2 Hz, 1H); 7.00 (d, J=1.6 Hz, 1H); 7.11-7.20 (m, 2H); 7.33-7.39 (m,2H); 7.58-7.61 (m, 1H).

Example 11(R,S)—N-[3-(1,1-Difluoro-2-{[6-({2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}ethyl)phenyl]urea

Obtained from Intermediate 56 (1.12 g, 2.15 mmol) by the proceduredescribed in Example 1. Purification by column chromatography withsilica gel, using methylene chloride/ethanol/ammonium hydroxide (40:8:1)as eluent gave(R,S)—N-[3-(1,1-difluoro-2-{[6-({2-hydroxy-2-[4-hydroxy-3-hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}ethyl)phenyl]-urea(0.49 g, 46%) as an off-white solid.

¹H-NMR (300 MHz, DMSO-D6): 1.20-1.26 (m, 4H); 1.32-1.47 (m, 4H);2.54-2.57 (m, 4H); 3.45 (t, J=6.6 Hz, 2H); 3.86 (t, J_(F-H)=13.9 Hz,2H); 4.46-4.51 (m, 3H); 4.94 (bs, 1H); 5.04 (bs, 1H); 5.92 (s, 2H); 6.68(d, J=8.2 Hz, 1H); 6.98 (dd, J₁=8.0, J₂=1.9 Hz, 1H); 7.03 (d, J=8.0 Hz,1H); 7.25 (d, J=1.9 Hz, 1H); 7.32 (t, J=7.8 Hz, 1H); 7.44-7.47 (m, 1H);7.65 (s, 1H); 8.74 (s, 1H).

MS (M+): 481.

Intermediate 57.1-bromo-3-{2-[(6-bromohexyl)oxy]-1,1-difluoroethyl}benzene

A solution of benzyl alcohol (3.2 mL, 30.9 mmol) in dimethylformamide(100 mL) was cooled to 0° C. and 60% sodium hydride (1.23 g, 30.9 mmol)was slowly added. The mixture was stirred at room temperature for 0.5hours, then cooled to 0° C. again and a solution of Intermediate 50(12.72 g, 20.6 mmol) in dimethylformamide (65 mL) was slowly added. Themixture was stirred 4 hours at room temperature. The crude reaction wascooled to 0° C. and water (3 mL) was added and then was concentrated.The residue was dissolved with methylene chloride (150 mL), washed withwater (2×75 mL) and brine (1×50 mL), dried (Na₂SO₄), and the solventremoved under reduced pressure. Purification by column chromatographywith silica gel and methylene chloride as eluent gave the title compound(5.1 g, 57%) as oil.

¹H NMR (300 MHz, CDCl₃): 1.25-1.36 (m, 4H); 1.50-1.62 (m, 4H); 3.43-3.52(m, 4H); 3.81 (t, J=12.8 Hz, 2H); 4.50 (s, 2H); 7.26-7.35 (m, 6H);7.43-7.46 (m, 1H); 7.57 (d, J=8.0 Hz, 1H); 7.68 (d, J=1.6 Hz, 1H).

Intermediate 58.[3-(2-{[6-(benzyloxy)hexyl]oxy}-1,1-difluoroethyl)phenyl]amine

Obtained from Intermediate 57 (5.04 g, 11.88 mmol) by the proceduredescribed in Intermediate 54. Purification by column chromatography withsilica gel and methylene chloride/methanol (from pure methylene chlorideto 99:1) as eluent gave the title compound (3.9 g, 90%) as oil.

¹H NMR (300 MHz, CDCl₃): 1.28-1.38 (m, 4H); 1.52-1.66 (m, 4H); 3.43-3.54(m, 4H); 3.80 (t, J=13.5 Hz, 2H); 4.50 (s, 2H); 6.73 (dd, J₁=8.0 Hz,J₂=1.6 Hz, 1H); 6.81-6.82 (m, 1H); 6.87 (d, J=7.7 Hz, 1H); 7.19 (t,J=7.8 Hz, 1H); 7.27-7.31 (m, 1H); 7.32-7.38 (m, 4H).

Intermediate 59. EthylN-({[3-(2-{[6-(benzyloxy)hexyl]oxy}-1,1-difluoroethyl)phenyl]-amino}carbonyl)glycinate

To a solution of Intermediate 58 (3.9 g, 10.7 mmol) in methylenechloride (35 mL) was added ethyl isocyanatoacetate (1.38 mL, 12.3 mmol).The mixture was stirred at room temperature for 5 hours. The crudereaction was cooled to 0° C. and then methanol (2.3 mL) was added. Themixture was stirred at room temperature for 0.5 hours and the solventwas removed under reduced pressure. Purification by columnchromatography using methylene chloride/methanol (from pure methylenechloride to 98:2) as eluent gave the title compound (5.1 g, 95%) as oil.

¹H NMR (300 MHz, CDCl₃): 1.27-1.36 (m, 7H); 1.49-1.65 (m, 4H); 3.51 (m,4H); 3.80 (t, J_(F-H)=12.9 Hz, 2H); 4.02 (s, 2H): 4.22 (q, J=7.2 Hz,2H); 4.53 (s, 2H); 7.13-7.18 (m, 2H); 7.30-7.36 (m, 6H): 7.58 (d, J=8.0Hz, 1H).

Intermediate 60.N-({[3-(2-{[6-(benzyloxy)hexyl]oxy)-1,1-difluoroethyl)phenyl]amino}carbonyl)glycine

To a solution of intermediate 59 (5.09 g, 10 mmol) in ethanol (30 mL)was added 2N NaOH (18 mL, 35 mmol). The mixture was stirred at roomtemperature for 3 hours. The crude reaction was concentrated and theresidue was diluted with ethyl acetate (50 mL) and washed with water(2×25 mL). The aqueous layer was acidified to pH 2 with HCl and thenextracted with ethyl acetate (2×50 mL). The organic layers were dried(Na₂SO₄) and the solvent removed under reduced pressure. The titledcompound was obtained (4.23 g, 88%).

¹H NMR (300 MHz, CDCl₃): 1.25-1.34 (m, 4H); 1.49-1.58 (m, 4H); 3.49 (t,J=6.6 Hz, 4H); 3.80 (t, J_(F-H)=12.9 Hz, 2H); 3.92 (s, 2H); 4.52 (s,2H); 5.81 (bs, 1H); 7.15 (d, J=7.4 Hz, 1H); 7.29-7.34 (m, 6H); 7.40 (d,J=1.9 Hz, 2H); 7.66 (bs, 1H).

Intermediate 61.3-[3-(2-{[6-(benzyloxy)hexyl]oxy}-1,1-difluoroethyl)phenyl]imidazolidine-2,4-dione

A solution of Intermediate 60 (3.42 g, 7.4 mmol), water (20 mL) andconcentrated HCl (5.5 mL) was heated at 140° C. for 12 hours. Thereaction was cooled. The crude was extracted with ethyl acetate (50 mL)and washed with saturated solution of sodium bicarbonate (2×20 mL),water (2×20 mL) and brine (1×20 mL), dried (Na₂SO₄) and concentrated.The titled compound was obtained (2.52 g, 76%) as oil.

1H NMR (300 MHz, CDCl₃): 1.33 (bs, 4H); 1.58 (bs, 4H); 3.43-3.54 (m,4H); 3.84 (t, J_(F-H)=13.0 Hz, 2H); 4.13 (s, 2H); 4.49 (s, 2H); 5.56(bs, 1H); 7.34 (bs, 6H); 7.53 (bs, 3H); 7.61 (s, 1H).

Intermediate 62.3-(3-{1,1-difluoro-2-[(6-hydroxyhexyl)oxy]ethyl}phenyl)imidazolidine-2,4-dione

To a solution of Intermediate 61 (2.52 g, 5.65 mmol) in ethanol (120 mL)was added palladium on charcoal (300 mg). The mixture was bidrogenatedat 40 psi for 4 hours. The catalyst was filtered through Celite and thesolvent removed under pressure to give the title compound (1.94 g, 96%)as oil.

¹H NMR (300 MHz, CDCl₃): 1.23-1.32 (m, 4H); 1.50-1.59 (m, 3H); 3.50-3.62(m, 4H); 3.73 (q, J=7.1 Hz, 1H); 3.86 (t, J_(F-H)=12.8 Hz, 2H); 4.17 (s,2H); 5.99 (bs, 1H); 7.52-7.56 (m, 4H); 7.61 (bs, 1H).

Intermediate 63.6-{2-[3-(2,5-dioximidazolidin-1-yl)phenyl]-2,2-difluoroethoxy}hexylmethanesulfonate

Intermediate 62 (1.94 g, 5.45 mmol) was dissolved in methylene chloride(15 mL) and triethylamine (1.21 mL, 8.72 mmol) was then added. Themixture was cooled to 0° C. and a solution of methanesulfonyl chloride(0.680 mL, 8.72 mmol) in methylene chloride (5 mL) was slowly added atthe same temperature. The mixture was stirred at room temperature for 16hours. The crude reaction was cooled to 0° C. and then 50% solutionwater/ammonium hydroxide (40 mL) was added. The organic layer was washedwith water (2×40 mL), brine (1×40 mL), dried (Na₂SO₄) and concentrated.The title compound was obtained (2.4 g, 100%) as oil.

¹H NMR (300 MHz, CDCl₃): 1.34-1.43 (m, 4H); 1.54-1.72 (m, 6H); 3.0 (s,3H); 3.53 (t, J=6.2 Hz, 2H); 3.86 (t, J_(F-H)=12.8 Hz, 2H); 4.17 (s,2H); 5.88 (bs, 1H); 7.54 (bs, 4H); 7.62 (bs, 1H).

Intermediate 64.3-(3-{2-[(6-{[2-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]amino}hexyl)oxy]-1,1-difluoroethyl}phenyl)imidazolidine-2,4-dione

To a solution of Intermediate 63 (2.4 g, 5.4 mmol) in dimethylformamide(30 mL) was added(R,S)-2-amino-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)ethanol (1.64 g,7.33 mmol) and tetrabutylammonium bromide (1.74 g, 5.4 mmol). Themixture was stirred at room temperature for 98 hours. The crude reactionwas concentrated and the residue was diluted with methylene chloride (50mL) and washed with water (2×25 mL). The organic layer was dried(Na₂SO₄) and the solvent removed under reduced pressure. Purification bycolumn chromatography using methylene chloride/ethanol/ammoniumhydroxide (100:8:1) as eluent gave the title compound (0.67 g, 22%) asoil.

¹H NMR (300 MHz, CDCl₃): 1.22-1.33 (m, 3H); 1.54 (s, 6H); 2.57-2.67 (m,3H); 2.82-2.87 (m, 1H); 3.52 (t, J=6.5 Hz, 2H); 3.69-3.76 (m, 2H);3.81-3.90 (m, 2H); 4.13 (s, 2H); 4.64 (dd, J₁=9.2 Hz, J₂=3.4 Hz, 1H);4.85 (s, 2H); 6.79 (d, J=8.5 Hz, 1H); 7.01 (s, 1H); 7.13 (dd, J₁=8.4 Hz,J₂=2.1 Hz, 1H); 7.28 (m, 1H); 7.51-7.56 (m, 2H); 7.62 (bs, 1H).

Example 12(R,S-)3-[3-(1,1-difluoro-2-{[6-({2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}ethyl)phenyl]imidazolidine-2,4-dione

Obtained from Intermediate 64 (0.67 g, 1.20 mmol) by the proceduredescribed in Example 1. Purification by column chromatography withsilica gel and methylene chloride/ethanol/ammonium hydroxide (40:8:1) aseluent gave3-[3-(1,1-difluoro-2-{[6-({2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}ethyl)phenyl]imidazolidine-2,4-dione(0.04 g, 10%) as oil.

¹H NMR (300 MHz, dimethylsulfoxide-D6): 1.15-1.30 (m, 4H); 1.35-1.45 (m,4H); 2.60-2.80 (m, 4H); 3.46-3.50 (m, 2H); 3.95 (t, J=13.9 Hz, 2H); 4.07(s, 2H); 4.47 (s, 2H); 4.60-4.70 (m, 1H); 6.72 (d, J=7.9 Hz, 1H); 7.01(d, J=8.2 Hz, 1H); 7.29 (s, 1H); 7.51-7.61 (m, 4H); 8.34 (bs, 1H).

Intermediate 65. 2-bromo-1-(3-methoxyphenyl)ethanone

To a solution of 1-(3-methoxyphenyl)ethanone (5.5 mL, 40 mmol) inchloroform (100 mL) was added dropwise a solution of bromine (2.05 mL,40 mmol) in chloroform (20 mL). The mixture was stirred at roomtemperature overnight. The solvent was removed under reduced pressure.The residue was diluted in methylene chloride (50 mL) and washed withwater (2×25 mL). The organic layer was dried (Na₂SO₄) and the solventremoved under reduced pressure. Purification by column chromatographyusing methylene chloride as eluent gave the title compound (8.44 g, 84%)as oil.

¹H NMR (300 MHz, CDCl₃): 3.9 (s, 3H); 4.5 (s, 2H); 7.14-7.18 (dd, J=7.8,3.2 Hz, 1H); 7.43 (t, J=8.0 Hz, 1H); 7.51-7.58 (m, 2H).

Intermediate 66. Ethyl(3-methoxyphenyl)(oxo)acetate

A suspension of selenium dioxide (4.08 g, 37 mmol) in ethanol (35 mL)was refluxed for 10 minutes and then, Intermediate 65 (8.44 g, 37 mmol)was added. The mixture was refluxed overnight. The cooled reaction wasfiltered through Celite and the solvent removed under reduced pressure.The residue was diluted with methylene chloride (50 mL), washed withwater (2×25 mL), dried (Na₂SO₄), and concentrated. Purification bycolumn chromatography with silica gel using methylene chloride as eluentgave the title compound (4.12 g, 53%) as oil.

¹H NMR (300 MHz, CDCl₃): 1.43 (t, J=7.1 Hz, 3H); 3.87 (s, 3H); 4.46 (q,J=7.3 Hz, 2H); 7.21 (dd, J=8.2, 2.7 Hz, 1H); 7.42 (t, J=8.0 Hz, 1H);7.54-7.59 (m, 2H).

Intermediate 67. Ethyl difluoro(3-methoxyphenyl)acetate

Obtained from Intermediate 66 (4.12 g, 20 mmol) by the proceduredescribed in Intermediate 1. Ethyl difluoro(3-methoxyphenyl)acetate wasobtained (4.35 g, 94%) as oil.

¹H NMR (300 MHz, CDCl₃): 1.31 (t, J=7.1 Hz, 3H); 3.84 (s, 3H); 4.29 (q,J=7.1 Hz, 2H); 7.02 (dd, J=8.2, 1.6 Hz, 1H); 7.13 (s, 1H); 7.19 (d,J=7.7 Hz, 1H); 7.37 (t, J=8.0 Hz, 1H).

Intermediate 68. 2,2-difluoro-2-(3-methoxyphenyl)ethanol

Obtained from Intermediate 67 (4.35 g, 19 mmol) by the proceduredescribed in Intermediate 2. The title compound was obtained (3.19 g,90%) as oil.

¹H NMR (300 MHz, CDCl₃): 3.84 (s, 3H); 3.97 (t, J=13.5 Hz, 2H);6.99-7.11 (m, 3H); 7.37 (t, J=8.0 Hz, 1H).

Intermediate 69.1-{2-[(6-bromohexyl)oxy]-1,1-difluoroethyl}-3-methoxybenzene

To a cooled solution of Intermediate 68 (3.19 g, 16.95 mmol) indimethylformamide (20 mL) was added 60% sodium hydride (1.36 g, 33.9mmol) and 1,6-dibromohexane (5.2 mL, 33.9 mmol). The mixture was stirredat room temperature for 2 hours. The crude was diluted with methylenechloride (50 mL) and washed with water (3×50 mL), dried (MgSO₄) andconcentrated. The excess of 1,6-dibromohexane was eliminated bydistillation at reduced pressure (P=0.15-0.18 mmHg, T=60-65° C.) and thecrude was purified by column chromatography with silica gel usingmethylene chloride as eluent. The title compound was obtained (3.41 g,57%) as oil.

¹H NMR (300 MHz, CDCl₃): 1.22-1.48 (m, 4H); 1.50-1.64 (m, 2H); 1.76-1.90(m, 2H); 3.38 (t, J=6.87 Hz, 2H); 3.52 (t, J=6.457 Hz, 2H); 3.78-3.87(m, 5H); 6.98 (dd, J=8.24 Hz. J=1.92 Hz, 1H); 7.05-7.10 (m, 2H); 7.34(t, J=7.97 Hz, 1H).

Intermediate 70.3-{6-[2,2-difluoro-2-(3-methoxyphenyl)ethoxy]hexyl}-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-one

Obtained from Intermediate 69 (3.41 g, 9.7 mmol) and intermediate 51(1.37 g, 5.49 mmol) by the procedure described in Intermediate 35.Purification by column chromatography with silica gel and hexane/ethylacetate (1:2) as eluent gave the title compound (1.96 g, 69%) as oil.

¹H NMR (300 MHz, CDCl₃): 1.22-1.41 (m, 4H); 1.49-1.63 (m, 4H); 1.54 (s,6H); 3.16-3.45 (m, 4H); 3.50-3.54 (m, 2H); 3.81-3.84 (m, 5H); 4.84 (s,2H); 5.40 (t, J=8.0 Hz, 1H); 6.84 (d, J=8.5 Hz, 1H); 6.96-7.14 (m, 5H);7.34 (t, J=7.9 Hz, 1H).

Intermediate 71.(R,S)-2-({6-[2,2-difluoro-2-(3-methoxyphenyl)ethoxy]hexyl}amino)-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)ethanol

Obtained from Intermediate 70 (1.96 g, 3.77 mmol) by the proceduredescribed in Intermediate 36. The title compound was obtained (1.78 g,96%) as oil.

1H NMR (300 MHz, CDCl₃): 1.22-1.38 (m, 4H); 1.49-1.63 (m, 4H); 1.53 (s,6H); 2.53-2.74 (m, 4H); 2.81-2.90 (m, 1H); 3.46-3.57 (m, 2H); 3.81-3.84(m, 5H); 4.60-4.70 (m, 1H); 4.84 (s, 2H); 6.79 (d, J=8.5 Hz, 1H);6.96-7.14 (m, 5H); 7.34 (t, J=7.9 Hz, 1H).

Example 13(R,S)-4-[2-({6-[2,2-difluoro-2-(3-methoxyphenyl)ethoxy]hexyl}amino)-1-hydroxyethyl]-2-(hydroxymethyl)phenol

Obtained from Intermediate 71 (1.78 g, 3.61 mmol) by the proceduredescribed in Example 1. Purification by column chromatography withsilica gel and methylene chloride/methanol/triethylamine (91:8:1) aseluent gave(R,S)-4-[2-({6-[2,2-difluoro-2-(3-methoxyphenyl)ethoxy]hexyl}amino)-1-hydroxyethyl]-2-(hydroxymethyl)phenol(1.52 g, 93%) as oil.

1H NMR (300 MHz, CDCl₃): 1.18-1.34 (m, 4H); 1.43-1.50 (m, 2H); 1.56-1.69(m, 2H); 2.85 (d, J=20.1 Hz, 4H); 3.48 (t, J=6.3 Hz, 2H); 3.72-3.87 (m,5H); 4.49 (s, 2H); 4.80 (bs, 1H); 6.70 (d, J=8.2 Hz, 1H); 6.87-7.32 (m,5H); 7.34 (t, J=7.8 Hz, 1H); 8.04 (bs, 1H).

Intermediate 72.8-(benzyloxy)-5-((1R)-1-{[tert-butyl(dimethyl)silyl]oxy}-2-{[6-(2,2-difluoro-2-phenylethoxy)hexyl]amino}ethyl)quinolin-2(1H)-one

To a solution of(8-(benzyloxy)-5-((1R)-2-bromo-1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)quinolin-2(1H)-one(4.80 g, 9.83 mmol) and Intermediate 9 (3.04 g, 11.8 mmol) indimethylsulfoxide (13.5 mL) was added sodium bicarbonate (2.49 g, 29.4mmol) and sodium iodide (2.22 g, 14.8 mmol). The mixture was heated at140° C. for 2 hours. After cooling, the reaction was diluted with water(40 mL) and extracted with diethyl ether (2×20 mL). The combined organicextracts were washed with water (2×10 mL) and brine (20 mL), dried(Na₂SO₄), and the solvent removed under reduced pressure. The titlecompound was obtained (6.40 g, 98%) as oil.

1H NMR (300 MHz, CDCl₃): 0.20-0.31 (m, 5H): 1.03-1.11 (m, 10H);1.38-1.49 (m, 5H); 1.63-1.80 (m, 5H); 2.75-2.95 (m, 2H); 3.08-3.15 (m,H); 3.66-3.73 (m, 2H); 3.98-4.07 (m, 2H); 5.35 (s, 2H); 6.85 (d, J=9.9Hz, 1H); 7.19 (d, J=8.5 Hz, 1H), 7.31-7.34 (m, 1H); 7.45 (s, 2H);7.58-7.65 (m, 6H); 7.69-7.71 (m, 2H); 8.50 (d, J=9.9 Hz, 1H).

Intermediate 73.8-(benzyloxy)-5-((1R)-2-{[6-(2,2-difluoro-2-phenylethoxy)hexyl]amino}-1-hydroxyethyl)quinolin-2(1H)-one

To a solution of intermediate 72 (6.4 g, 9.63 mmol) in tetrahydrofuran(60 mL) was added tetra-n-butyl ammonium fluoride (5.02 g, 19.26 mmol).The mixture was stirred at room temperature overnight. The solvent wasremoved under reduced pressure. Purification by column chromatographyusing methylene chloride/methanol (from 95:5 to 85:15) as eluent gave8-(benzyloxy)-5-((1R)-2-{[6-(2,2-difluoro-2-phenylethoxy)hexyl]amino}-1-hydroxyethy)quinolin-2(1H)-one(1.1 g, 20%) as oil.

MS (M+): 550

Example 145-((1R)-2-{[6-(2,2-difluoro-2-phenylethoxy)hexyl]amino}-1-hydroxyethyl)-8-hydroxyquinolin-2(1H)-one

Obtained from intermediate 73 (1.10 g, 2.0 mmol) by the proceduredescribed in Example 5. The resulting oil was purified by columnchromatography with silica gel eluting with methylene chloride/methanol(95:5) to give the title compound (0.50 g, 54%) as oil.

¹H-NMR (300 MHz, dimethylsulfoxide-D6); 1.15-1.35 (m, 5H); 1.40-1.50 (m,3H); 1.55-1.65 (m, 2H); 2.80-3.02 (m, 6H): 3.88-3.98 (m, 2H); 5.35-5.45(m, 1H): 6.55 (d, J=9.4 Hz, 1H); 7.00 (d, J=7.7 Hz, 1H); 7.15 (d, J=7.4Hz, 1H): 7.45-7.62 (m, 5H); 8.26 (d, J=9.6 Hz, 1H).

Intermediate 74.(1R)-2-{[4,4-Difluoro-6-(4-phenylbutoxy)hexyl]amino}-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)ethanol

Obtained from Intermediate 17 (0.39 g, 1.38 mmol) and(R)-2-amino-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)ethanol (0.62 g,2.77 mmol) by the procedure described in Intermediate 18. The titlecompound was obtained (0.42 g, 60%) as oil and was used in the next stepwithout further purification.

Example 154-((1R)-2-{[4,4-Difluoro-6-(4-phenylbutoxy)hexyl]amino}-1-hydroxy-ethyl)-2-(hydroxymethyl)phenol

Obtained from Intermediate 74 (0.41 g, 0.83 mmol) by the proceduredescribed in Example 1. The resulting oil was purified bysemi-preparative HPLC to give the title compound (0.12 g, 31%) as oil.

¹H-NMR (300 MHz, Cl₃CD): 1.54-1.63 (m, 4H); 1.82-1.90 (m, 4H); 2.01-2.12(m, 4H); 2.55-2.61 (m, 4H); 3.37 (t, J=6.0 Hz, 2H); 3.50 (t, J=6.0 Hz,2H); 4.38 (bs, 2H); 4.78 (bs, 1H); 6.64 (bs, 1H); 6.83 (bs, 1H); 6.95(bs, 1H); 7.12-7-26 (m, 5H); 8.34 (bs, 1H).

MS (M+): 451.

Intermediate 75. 3-Oxo-3-phenylpropyl acetate

To a solution of 3-chloro-1-phenylpropan-1-one (1.0 g, 5.93 mmol) inacetic acid (8 mL) was added sodium acetate (2.43 g, 29.7 mmol) andpotassium iodide (100 mg). The mixture was heated in a sealed tube at130° C. overnight. After cooling, the reaction was diluted with water(20 mL) and extracted with methylene chloride (3×20 mL). The combinedorganic extracts were washed with water (2×50 mL), saturated solution ofsodium bicarbonate (2×50 mL) and brine (20 mL), dried (Na₂SO₄), and thesolvent removed under reduced pressure. The title compound was obtained(1.0 g, 88%) as an orange solid.

¹H-NMR (300 MHz, Cl₃CD): 2.03 (s, 3H), 3.32 (t, J=6.0 Hz, 2H); 4.52 (t,J=6.0 Hz, 2H); 7.40-7.63 (m, 3H); 7.89-8.02 (m, 2H).

MS (M+): 192.

Intermediate 76. 3,3-Difluoro-3-phenylpropyl acetate

To a suspension of Intermediate 75 (1.0 g, 5.20 mmol) inbis(2-methoxyethyl)aminosulfur trifluoride (Deoxofluor®) (1.7 mL, 7.80mmol) was added boron trifluoride dimethyl ether complex (99 μL, 0.78mmol). The mixture was heated overnight at 85° C. and under argon. Aftercooling to 0° C., the reaction was diluted with methylene chloride (10mL) and then, saturated solution of sodium bicarbonate (20 mL) was addedvery slowly. The mixture was extracted with methylene chloride (3×20mL). The combined organic phase was washed with water (2×20 mL), dried(Na₂SO₄), and the solvent removed under reduced pressure. Purificationby column chromatography with silica gel eluting with n-hexanetethylacetate (from pure n-hexane to 6:4) gave the title compound (0.30 g,30%) as orange oil.

¹H-NMR (300 MHz, Cl₃CD): 1.94 (s, 3H): 2.47-2.57 (m, 2H); 4.22 (t, J=6.0Hz, 2H); 7.42-7.48 (m, 5H).

Intermediate 77. 3,3-Difluoro-3-phenylpropan-1-ol

To a suspension of Intermediate 76 (0.30 g, 1.40 mol) in ethanol (4 mL)was added a solution of 35% sodium hydroxide (1 mL). The mixture wasstirred at room temperature for 2 hours. The crude reaction was dilutedwith methylene chloride (50 mL), washed with water (1×30 ML) and 1Nhydrochloric acid (2×30 mL), dried (Na₂SO₄), and the solvent removedunder reduced pressure. The title compound was obtained (0.22 g, 89%) asorange oil, and was used in the next step without further purification.

¹H-NMR (300 MHz, Cl₃CD): 2.36-2.52 (m, 2H); 3.85 (t, J=6.0 Hz, 2H);7.44-7.51 (m, 5H).

Intermediate 78. 6-Bromohexyl 3,3-difluoro-3-phenylpropyl ether

Obtained from Intermediate 77 (0.41 g, 0.83 mmol) by the proceduredescribed in Intermediate 69. The resulting oil was purified by columnchromatography with silica gel eluting with n-hexane/ethyl acetate (frompure n-hexane to 9:1) to give the title compound (0.85 g of 66% purity,64%) as oil.

¹H-NMR (300 MHz, Cl₃CD): 1.42-1.47 (m, 4H); 1.81-1.89 (m, 4H); 2.46-2.51(m, 2H); 3.32-3.43 (m, 4H); 3.54 (t, J=6.0 Hz, 2H); 7.42-7.47 (m, 5H).

Intermediate 79.(R,S)-3-[6-(3,3-Difluoro-3-phenylpropoxy)hexyl]-5-(2,2-dimethyl-4H-1,3-benzodioxin-6yl)-1,3-oxazolidin-2-one

Obtained from Intermediate 78 (0.85 g, of 66% purity, 1.86 mmol) andIntermediate 51 (0.93 g, 3.72 mmol) by the procedure described inIntermediate 35. Purification by column chromatography with silica geleluting with n-hexane/ethyl acetate (from pure n-hexane to 1:1) gave thetitle compound (0.44 g, 47%) as oil.

¹H-NMR (300 MHz, Cl₃CD): 1.32-1.61 (m, 8H); 1.54 (s, 6H); 2.46 (h, J=9.0Hz, 2H), 3.32-3.44 (m, 4H); 3.54 (t, J=6.0 Hz, 2H); 3.73 (q, J=6.0 Hz,2H); 4.84 (s, 2H); 5.37-5.43 (m, 1H); 6.83 (d, J=9.0 Hz, 1H); 7.00 (s,1H); 7.12 (d, J=9.0 Hz, 1H); 7.41-7.47 (m, 5H).

MS (M+): 503.

Example 16(R,S)-4-(2-{[6-(3,3-Difluoro-3-phenylpropoxy)hexyl]amino}-1-hydroxyethyl)-2-(hydroxymethyl)phenol

Obtained from Intermediate 79 (0.44 g, 1.0 mmol) by the proceduresdescribed in Intermediate 36 and Example 1. The resulting oil waspurified by semi-preparative HPLC to give the title compound (44 mg,10%) as oil.

¹H-NMR (300 MHz, Cl₃CD): 1.22-1.66 (m, 8H); 1.87-2.03 (m, 4H); 2.40-2.54(m, 4H); 3.29-3.38 (m, 2H); 3.50-3.56 (m, 2H); 4.49 (bs, 2H); 4.83 (bs,1H); 6.68-6.89 (m, 1H); 6.91-6.93 (m, 1H); 7.01 (bs, 1H); 7.38-7.49 (m,5H).

MS (M+): 437.

Intermediate 80. Allyl 2,2-difluoro-2-phenylethyl ether

Obtained from Intermediate 6 (10.0 g, 63 mmol) and allyl bromide (6.5mL, 76 mmol) by the procedure described in Intermediate 11. Purificationby column chromatography with silica gel eluting with methylene chloridegave the title compound (11.2 g, 89%) as oil.

¹H-NMR (400 MHz, Cl₃CD): 3.76-3.90 (m, 2H); 3.98-4.12 (m, 2H); 5.14-5.32(m, 2H); 5.70-5.90 (m, 1H); 7.35-7.59 (m, 5H).

Intermediate 81. 3-(2,2-Difluoro-2-phenylethoxy)propan-1-ol

Obtained from intermediate 80 (10.6 g, 53 mmol) by the proceduredescribed in Intermediate 12. Purification by column chromatography withsilica gel eluting with ethyl acetate/n-hexane (from 1:4 to pure ethylacetate) gave the title compound (10.7 g, 96%) as oil.

¹H-NMR (200 MHz, Cl₃CD): 1.80 (qt, J=5.8 Hz, 2H), 3.66-3.73 (m, 4H);3.86 (t, J_(F-H)=12.9 Hz, 2H), 7.43-7.54 (m, 5H).

Intermediate 82. 3-(2,2-Difluoro-2-phenylethoxy)propanal

Obtained from Intermediate 81 (3.0 g, 14.4 mmol) by the proceduredescribed in Intermediate 13. Purification by column chromatography withsilica gel eluting with methylene chloride gave the title compound (1.86g, 60%) as oil.

¹H-NMR (200 MHz, Cl₃CD): 2.67 (td, J1=6.0 Hz, J2=1.8 Hz, 2H); 3.89 (t,J_(F-H)=13.3 Hz, 2H); 3.89 (t, J=6.0 Hz, 2H); 7.40-7.53 (m, 5H); 9.72(t, J=1.8 Hz, 1H).

Intermediate 83. 1-(2,2-Difluoro-2-phenylethoxy)hept-6-en-3-ol

Obtained from Intermediate 82 (1.86 g, 8.7 mmol) by the proceduredescribed in Intermediate 14. Purification by column chromatography withsilica gel eluting with ethyl acetate/n-hexane (1:6) gave the titlecompound (1.24 g, 53%) as oil.

¹H-NMR (200 MHz, Cl₃CD): 1.46-1.88 (m, 4H); 2.06-2.20 (m, 2H); 3.63-3.83(m, 3H); 3.86 (t, J_(F-H)=12.9 Hz, 2H); 4.92-5.07 (m, 2H); 5.75-5.92 (m,1H); 7.43-7.55 (m, 5H).

Intermediate 84. 1-(2,2-Difluoro-2-phenylethoxy)hept-6-en-3-one

Obtained from Intermediate 83 (4.3 g, 15.8 mmol) by the proceduredescribed in Intermediate 13. Purification by column chromatography withsilica gel eluting with ethyl acetate/n-hexane (1:5) gave the titlecompound (1.82 g, 43%) as oil.

¹H-NMR (200 MHz, Cl₃CD): 2.25-2.34 (m, 2H); 2.48 (dt, J1=6.6 Hz, J2=1.6Hz, 2H); 2.64 (t, J=6.0 Hz, 2H); 3.81 (t, J=6.0 Hz, 2H); 3.87 (t,J_(F-H)=13.3 Hz, 2H); 4.94-5.06 (m, 2H); 5.67-5.87 (m, 1H); 7.41-7.52(m, 5H).

Intermediate 85. 3,3-Difluorohept-6-en-1-yl 2,2-difluoro-2-phenylethylether

To a cooled solution of Intermediate 84 (1.6 g, 10 mmol) in methylenechloride (8 mL) was added CAST (4.70 ml, 40 mmol). The mixture wasstirred overnight at 40° C. and under argon. The crude reaction wasdiluted with methylene chloride (50 mL), washed with cool water (25 mL)and saturated solution of sodium bicarbonate (2×25 mL), dried (Na₂SO₄),and the solvent removed under reduced pressure. The residue was purifiedby column chromatography on silica gel using ethyl acetate/n-hexane(from 1:8 to 1:6) as eluent. The title compound was obtained (600 mg,21%) as oil.

¹H-NMR (300 MHz, Cl₃CD): 1.80-1.94 (m, 2H); 2.08-2.24 (m, 4H); 3.71 (t,J=6.5 Hz, 2H); 3.85 (t, J_(F-H)=13.0 Hz, 2H); 4.97-5.06 (m, 2H);5.70-5.81 (m, 1H) 7.44-7.50 (m, 5H).

Intermediate 86. 6-(2,2-Difluoro-2-phenylethoxy)-4,4-difluorohexanal

Obtained from Intermediate 85 (0.80 g, 2.7 mmol) by the proceduredescribed in Intermediate 17. Purification by column chromatography withsilica gel eluting with ethyl acetate/n-hexane (1:5) gave the titlecompound (0.48 g, 60%) as oil.

¹H-NMR (300 MHz, Cl₃CD): 2.05-2.19 (m, 4H), 2.61 (t, J=7.6 Hz, 2H); 3.71(t, J=6.2 Hz, 2H); 3.86 (t, J_(F-H)=13.0 Hz, 2H); 7.44-7.52 (m, 5H);9.72 (s, 1H).

Intermediate 87.(R)-2-{[6-(2,2-Difluoro-2-phenylethoxy)-4,4-difluorohexyl]amino}-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)ethanol

Obtained from Intermediate 86 (0.49 g, 1.66 mmol) and(R)-2-amino-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)ethanol (0.74 g,3.31 mmol) by the procedure described in Intermediate 18. The titlecompound was obtained (0.50 g, 83%) as oil and was used in the next stepwithout further purification.

Example 17(R)-4-(2-{[6-(2,2-Difluoro-2-phenylethoxy)-4,4-difluorohexyl]amino}-1-hydroxyethyl)-2-(hydroxymethyl)phenol

Obtained from Intermediate 87 (0.50 g, 1.0 mmol) by the proceduredescribed in Example 1. Purification by column chromatography withsilica gel, eluting with methylene chloride/methanol/ammonium hydroxide(from 200:20:1 to 150:20:1) gave(R)-4-(2-{[6-(2,2-difluoro-2-phenylethoxy)-4,4-difluorohexyl]amino}-1-hydroxyethyl)-2-(hydroxymethyl)phenol(0.12 g, 26% overall yield) as oil.

¹H-NMR (300 MHz, Cl₃CD): 1.59-1.90 (m, 4H); 2.03-2.18 (m, 2H); 2.58-2.79(m, 4H); 3.70 (t, J=6.3 Hz, 2H); 3.84 (t, J_(F-H)=13.3 Hz, 2H); 4.28(bs, 4H), 4.55-4.59 (m, 1H); 4.69 (s, 2H); 6.78 (d, J=8.0 Hz, 1H); 6.95(s, 1H); 7.05 (d, J=8.0 Hz, 1H); 7.32-7.50 (m, 5H).

MS (M+): 459.

Intermediate 88. Ethyl 2,2-difluoro-3-hydroxy-3-phenylpropanoate

To a solution of benzaldehyde (3.0 g, 28 mmol) in anhydroustetrahydrofuran (80 mL) was added zinc (2.4 g, 36 mmol). The mixture washeated at 75° C. under inert atmosphere and ethyl2-bromo-2,2-difluoroacetate (4.4 mL, 34 mmol) was slowly added. Themixture was heated under the same conditions for 2 hours. After cooling,2N hydrochloric acid (25 mL) was added until the complete consumption ofunreacted zinc. The solvent was removed under reduced pressure. Thecrude reaction was dissolved in ethyl ether (150 mL) and washed withbrine (2×100 mL), dried (Na₂SO₄), and the solvent removed under reducedpressure. The title compound was obtained (6.4 g, 99%) as yellow oil andwas used in the next step without further purification.

¹H-NMR (300 MHz, Cl₃CD): 1.28 (t, J=7.1 Hz, 3H); 3.22 (bs, 1H); 4.29 (q,J=7.1 Hz, 2H); 5.15 (dd, J_(1(F-H))=15.7 Hz, J₂=8.0 Hz, 1H); 7.37-7.44(m, 5H).

Intermediate 89. Ethyl2,2-difluoro-3-{[(methylthio)carbonothioyl]oxy}-3-phenyl propanoate

To a solution of intermediate 88 (6.4 g, 28 mmol) in dimethylformamide(50 mL) was added 1,5-diazabicyclo(5,4,0)undec-5-ene (DBU) (17.0 mL,0.11 mol) and carbon disulfide (16.9 mL, 0.28 mol). The mixture wasstirred under inert atmosphere and at room temperature for 1 hour and 30minutes. Then, methyl iodide was added (17.5 mL, 280 mmol) and themixture stirred under the same conditions for 1 hour and 30 minutes. Thesolvent was eliminated under reduced pressure. The crude was treatedwith water (200 mL) and extracted with ethyl acetate (3×100 mL). Thecombined organic phase was washed with brine (2×100 mL), dried (Na₂SO₄),and the solvent removed under reduced pressure. Purification by columnchromatography with silica gel eluting with ethyl acetate/n-hexane (frompure n-hexane to 1:9) gave the title compound (6.8 g, 76%) as oil.

¹H-NMR (300 MHz, Cl₃CD): 1.30 (t, J=7.1 Hz, 3H); 2.57 (s, 3H); 4.33 (q,J=7.1 Hz, 2H); 6.97 (dd, J_(1(F-H))=16.5 Hz, J₂=8.0 Hz, 1H); 7.38-7.44(m, 5H).

Intermediate 90. Ethyl 2,2-difluoro-3-phenylpropanoate

To a solution of intermediate 89 (8.0 g, 25 mmol) in dioxane (100 mL)were added diphenylphospine oxide (5.0 g, 25 mmol) and tert-butylperoxide (2.0 mL, 11 mmol). The mixture was heated at 110° C. underinert atmosphere for 48 hours. After cooling, the solvent was removedunder reduced pressure. Purification by column chromatography withsilica gel eluting with ethyl acetate/n-hexane (1:8) gave the titlecompound (2.2 g, 42%) as oil.

¹H-NMR (300 MHz, Cl₃CD): 1.26 (t, J=7.1 Hz, 3H): 3.38 (t, J_(F-H)=16.3Hz, 2H); 4.24 (q, J=7.1 Hz, 2H); 7.24-7.33 (m, 5H).

Intermediate 91. 2,2-Difluoro-3-phenylpropan-1-ol

To a cooled solution of Intermediate 90 (2.2 g, 10.3 mmol) in methanol(30 mL) was added sodium borohydride (1.94 g, 51 mmol). The mixture wasstirred at 5° C. for 20 minutes and at room temperature for 2 hours. Tothe crude reaction was added water (1 mL) and the solvents reduced underreduced pressure. The residue was dissolved in ethyl acetate (50 mL) andwashed with brine (2×25 mL), dried (Na₂SO₄), and concentrated.Purification by column chromatography with silica gel eluting with ethylacetate/n-hexane 1:5 gave the title compound (0.75 g, 42%) as oil

¹H-NMR (300 MHz, Cl₃CD): 1.87 (bs, 1H); 3.25 (t, J_(F-H)=16.5 Hz, 2H);3.67 (t, J_(F-H)=12.5 Hz, 2H); 7.27-7.36 (m, 5H).

Intermediate 92. 6-Bromohexyl 2,2-difluoro-3-phenylpropyl ether

Obtained from Intermediate 91 (0.75 g, 4.36 mmol) by the proceduredescribed in Intermediate 69. Purification by column chromatography withsilica gel eluting with n-hexane/ethyl acetate (from pure n-hexane to40:1) gave the title compound (0.53 g, 36%) as oil.

¹H-NMR (300 MHz, Cl₃CD): 1.40-1.52 (m, 4H); 1.57-1.68 (m, 2H); 1.83-1.94(m, 2H); 3.23 (t, J_(F-H)=16.5 Hz, 2H); 3.39-3.53 (m, 6H); 7.28-7.40 (m,5H).

Intermediate 93.(R,S)-3-[6-(2,2-Difluoro-3-phenylpropoxy)hexyl]-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-one

Obtained from Intermediate 92 (0.53 g, 1.58 mmol) and Intermediate 51(0.38 g, 1.52 mmol) by the procedure described in Intermediate 35.Purification by column chromatography with silica gel eluting withn-hexane/ethyl acetate (from 5:1 to 1:1) gave the title compound (0.30g, 39%) as oil.

¹H-NMR (300 MHz, Cl₃CD): 1.33-1.44 (m, 4H); 1.52-1.67 (m, 4H); 1.54 (s,6H); 3.23 (t, J=16.8 Hz, 2H); 3.31-3.52 (m, 7H); 3.87 (t, J=8.0 Hz, 1H);4.84 (s, 2H); 5.40 (t, J=8.0 Hz, 1H); 6.82 (d, J=8.5 Hz, 1H); 7.01 (s,1H); 7.12 (dd, J1=8.5 Hz, J2=1.9 Hz, 1H); 7.27-7.33 (m, 5H).

MS (M+): 503.

Example 18(R,S)-4-(2-{[6-(2,2-difluoro-3-phenylpropoxy)hexyl]amino}-1-hydroxyethyl)-2-(hydroxymethyl)phenol, hydrochloride

A solution of Intermediate 93 (30 mg, 0.06 mmol) in dioxane (1 mL) andconcentrated hydrochloric acid (0.1 mL) was stirred at room temperaturefor 2 hours. The solvent was removed under reduced pressure.Purification by column chromatography with silica gel eluting withmethylene chloride/methanol (from 15:1 to 10:1) gave the title compound(5 mg, 19%) as oil.

¹H-NMR (300 MHz, Cl₃CD): 1.21-1.44 (m, 4H); 1.48-1.68 (m, 4H); 2.66-2.76(m, 4H); 3.21 (t, J_(F-H)=16.5 Hz, 2H); 3.41-3.50 (m, 4H); 4.58 (bs,8H); 6.72 (d, J=7.7 Hz, 1H); 6.93-6.98 (m, 2H); 7.23-7.36 (m, 5H).

MS (M+): 437

Pharmaceutical Compositions

The pharmaceutical formulations may conveniently be presented in unitdosage form and may be prepared by any of the methods well known in theart of pharmacy. All methods include the step of bringing the activeingredient(s) into association with the carrier. In general theformulations are prepared by uniformly and intimately bringing intoassociation the active ingredient with liquid carriers or finely dividedsolid carriers or both and then, if necessary, shaping the product intothe desired formulation.

Formulations of the present invention suitable for oral administrationmay be presented as discrete units such as capsules, cachets or tabletseach containing a predetermined amount of the active ingredient; as apowder or granules; as a solution or a suspension in an aqueous liquidor a non-aqueous liquid: or as an oil-in-water liquid emulsion or awater-in-oil liquid emulsion. The active ingredient may also bepresented as a bolus, electuary or paste.

A syrup formulation will generally consist of a suspension or solutionof the compound or salt in a liquid carrier for example, ethanol, peanutoil, olive oil, glycerine or water with flavouring or colouring agent.

Where the composition is in the form of a tablet, any pharmaceuticalcarrier routinely used for preparing solid formulations may be used.Examples of such carriers include magnesium stearate, talc, gelatine,acacia, stearic acid, starch, lactose and sucrose. A tablet may be madeby compression or moulding, optionally with one or more accessoryingredients. Compressed tablets may be prepared by compressing in asuitable machine the active ingredient in a free-flowing form such as apowder or granules, optionally mixed with a binder, lubricant, inertdiluent, lubricating, surface active or dispersing agent.

Moulded tablets may be made by moulding in a suitable machine a mixtureof the powdered compound moistened with an inert liquid diluent. Thetablets may optionally be coated or scored and may be formulated so asto provide slow or controlled release of the active ingredient therein.

Where the composition is in the form of a capsule, any routineencapsulation is suitable, for example using the aforementioned carriersin a hard gelatine capsule. Where the composition is in the form of asoft gelatine capsule any pharmaceutical carrier routinely used forpreparing dispersions or suspensions may be considered, for exampleaqueous gums, celluloses, silicates or oils, and are incorporated in asoft gelatine capsule. Dry powder compositions for topical delivery tothe lung by inhalation may, for example, be presented in capsules andcartridges of for example gelatine or blisters of for example laminatedaluminium foil, for use in an inhaler or insufflator. Formulationsgenerally contain a powder mix for inhalation of the compound of theinvention and a suitable powder base (carrier substance) such as lactoseor starch. Use of lactose is preferred.

Each capsule or cartridge may generally contain between 2 μg and 150 μgof each therapeutically active ingredient. Alternatively, the activeingredient (s) may be presented without excipients.

Packaging of the formulation may be suitable for unit dose or multi-dosedelivery. In the case of multi-dose delivery, the formulation can bepre-metered or metered in use. Dry powder inhaler's are thus classifiedinto three groups: (a) single dose, (b) multiple unit dose and (c) multidose devices.

For inhalers of the first type, single doses have been weighed by themanufacturer into small containers, which are mostly hard gelatinecapsules. A capsule has to be taken from a separate box or container andinserted into a receptacle area of the inhaler. Next, the capsule has tobe opened or perforated with pins or cutting blades in order to allowpart of the inspiratory air stream to pass through the capsule forpowder entrainment or to discharge the powder from the capsule throughthese perforations by means of centrifugal force during inhalation.After inhalation, the emptied capsule has to be removed from the inhaleragain. Mostly, disassembling of the inhaler is necessary for insertingand removing the capsule, which is an operation that can be difficultand burdensome for some patients.

Other drawbacks related to the use of hard gelatine capsules forinhalation powders are (a) poor protection against moisture uptake fromthe ambient air, (b) problems with opening or perforation after thecapsules have been exposed previously to extreme relative humidity,which causes fragmentation or indenture, and (c) possible inhalation ofcapsule fragments. Moreover, for a number of capsule inhalers,incomplete expulsion has been reported (e. g. Nielsen at al, 1997).

Some capsule inhalers have a magazine from which individual capsules canbe transferred to a receiving chamber, in which perforation and emptyingtakes place, as described in WO 92/03175. Other capsule inhalers haverevolving magazines with capsule chambers that can be brought in linewith the air conduit for dose discharge (e.g. WO91/02558 and GB2242134). They comprise the type of multiple unit dose inhalers togetherwith blister inhalers, which have a limited number of unit doses insupply on a disk or on a strip.

Blister inhalers provide better moisture protection of the medicamentthan capsule inhalers. Access to the powder is obtained by perforatingthe cover as well as the blister foil, or by peeling off the cover foil.When a blister strip is used instead of a disk, the number of doses canbe increased, but it is inconvenient for the patient to replace an emptystrip. Therefore, such devices are often disposable with theincorporated dose system, including the technique used to transport thestrip and open the blister pockets.

Multi-dose inhalers do not contain pre-measured quantities of the powderformulation, They consist of a relatively large container and a dosemeasuring principle that has to be operated by the patient. Thecontainer bears multiple doses that are isolated individually from thebulk of powder by volumetric displacement. Various dose measuringprinciples exist, including rotatable membranes (e. g. EP0069715) ordisks (e. g. GB 2041763; EP 0424790; DE 4239402 and EP 0674533),rotatable cylinders (e. g. EP 0166294; GB 2165159 and WO 92/09322) androtatable frustums (e. g. WO 92/00771), all having cavities which haveto be filled with powder from the container. Other multi dose deviceshave measuring slides (e. g. U.S. Pat. No. 5,201,308 and WO 97/00703) ormeasuring plungers with a local or circumferential recess to displace acertain volume of powder from the container to a delivery chamber or anair conduit e. g. EP 0505321, WO 92/04068 and WO 92/04928.

Reproducible dose measuring is one of the major concerns for multi doseinhaler devices. The powder formulation has to exhibit good and stableflow properties, because filling of the dose measuring cups or cavitiesis mostly under the influence of the force of gravity. For reloadedsingle dose and multiple unit dose inhalers, the dose measuring accuracyand reproducibility can be guaranteed by the manufacturer. Multi doseinhalers on the other hand, can contain a much higher number of doses,whereas the number of handlings to prime a dose is generally lower.

Because the inspiratory air stream in multi-dose devices is oftenstraight across the dose measuring cavity, and because the massive andrigid dose measuring systems of multi dose inhalers can not be agitatedby this inspiratory air stream, the powder mass is simply entrained fromthe cavity and little de-agglomeration is obtained during discharge.

Consequently, separate disintegration means are necessary. However inpractice, they are not always part of the inhaler design. Because of thehigh number of doses in multi-dose devices, powder adhesion onto theinner walls of the air conduits and the de-agglomeration means must beminimized and/or regular cleaning of these parts must be possible,without affecting the residual doses in the device. Some multi doseinhalers have disposable drug containers that can be replaced after theprescribed number of doses has been taken (e. g. WO 97/000703). For suchsemi-permanent multi dose inhalers with disposable drug containers, therequirements to prevent drug accumulation are even more strict.

Apart from applications through dry powder inhalers the compositions ofthe invention can be administered in aerosols which operate viapropellant gases or by means of so-called atomisers, via which solutionsof pharmacologically-active substances can be sprayed under highpressure so that a mist of inhalable particles results. The advantage ofthese atomisers is that the use of propellant gases can be completelydispensed with. Such atomisers are described, for example, in PCT PatentApplication No. WO 91/14468 and international Patent Application No. WO97/12687, reference here being made to the contents thereof.

Spray compositions for topical delivery to the lung by inhalation mayfor example be formulated as aqueous solutions or suspensions or asaerosols delivered from pressurised packs, such as a metered doseinhaler, with the use of a suitable liquefied propellant. Aerosolcompositions suitable for inhalation can be either a suspension or asolution and generally contain the active ingredient (s) and a suitablepropellant such as a fluorocarbon or hydrogen-containingchlorofluorocarbon or mixtures thereof, particularly hydrofluoroalkanes,e. g. dichlorodifluoromethane, trichlorofluoromethane,dichlorotetrafluoroethane, especially 1,1,1,2-tetrafluoroethane,1,1,1,2,3,3,3-heptafluoro-n-propane or a mixture thereof. Carbon dioxideor other suitable gas may also be used as propellant.

The aerosol composition may be excipient free or may optionally containadditional formulation excipients well known in the art such assurfactants eg oleic acid or lecithin and cosolvens eg ethanol.Pressurised formulations will generally be retained in a canister (eg analuminium canister) closed with a valve (eg a metering valve) and fittedinto an actuator provided with a mouthpiece.

Medicaments for administration by inhalation desirably have a controlledparticle size. The optimum particle size for inhalation into thebronchial system is usually 1-10μ, preferably 2-5μ. Particles having asize above 20μ are generally too large when inhaled to reach the smallairways. To achieve these particle sizes the particles of the activeingredient as produced may be size reduced by conventional means eg bymicronisation. The desired fraction may be separated out by airclassification or sieving. Preferably, the particles will becrystalline.

Achieving a high dose reproducibility with micronised powders isdifficult because of their poor flowability and extreme agglomerationtendency. To improve the efficiency of dry powder compositions, theparticles should be large while in the inhaler, but small whendischarged into the respiratory tract. Thus, an excipient such aslactose or glucose is generally employed. The particle size of theexcipient will usually be much greater than the inhaled medicamentwithin the present invention. When the excipient is lactose it willtypically be present as milled lactose, preferably crystalline alphalactose monohydrate. Pressurized aerosol compositions will generally befilled into canisters fitted with a valve, especially a metering valve.Canisters may optionally be coated with a plastics material e. g. afluorocarbon polymer as described in W096/32150. Canisters will befitted into an actuator adapted for buccal delivery.

Typical compositions for nasal delivery include those mentioned abovefor inhalation and further include non-pressurized compositions in theform of a solution or suspension in an inert vehicle such as wateroptionally in combination with conventional excipients such as buffers,anti-microbials, tonicity modifying agents and viscosity modifyingagents which may be administered by nasal pump.

Typical dermal and transdermal formulations comprise a conventionalaqueous or non-aqueous vehicle, for example a cream, ointment, lotion orpaste or are in the form of a medicated plaster, patch or membrane.

Preferably the composition is in unit dosage form, for example a tablet,capsule or metered aerosol dose, so that the patient may administer asingle dose.

Each dosage unit contains suitably from 1 μg to 100 μg, and preferablyfrom 5 μg to 50 μg of a β2-agonist according to the invention.

The amount of each active which is required to achieve a therapeuticeffect will, of course, vary with the particular active, the route ofadministration, the subject under treatment, and the particular disorderor disease being treated.

The active ingredients may be administered from 1 to 6 times a day,sufficient to exhibit the desired activity. Preferably, the activeingredients are administered once or twice a day.

The compositions of the invention can optionally comprise one or moreadditional active substances which are known to be useful in thetreatment of respiratory disorders, such as PDE4 inhibitors,corticosteroids or glucocorticoids and/or anticholinergics.

Examples of suitable PDE4 inhibitors that can be combined withβ2-agonists are denbufylline, rolipram, cipamfyiline, arofyiline,filaminast, piciamilast, mesopram, drotaverine hydrochloride,lirimilast, roflumilast, cilomilast,6-[2-(3,4-Diethoxyphenyl)thiazol-4-yl]pyridine-2-carboxylic acid,(R)-(+)-4-[2-(3-Cyclopentyloxy-4-methoxyphenyl)-2-phenylethyl]pyridine,N-(3,5-Dichloro-4-pyridinyl)-2-[1-(4-fluorobenzyl)-5-hydroxy-1H-indol-3-yl]-2-oxoacetamide,9-(2-Fluorobenzyl)-N6-methyl-2-(trifluoromethyl)adenine,N-(3,5-Dichloro-4-pyridinyl)-8-methoxyquinoline-5-carboxamide,N-[9-Methyl-4-oxo-1-phenyl-3,4,6,7-tetrahydropyrrolo[3,2,1-jk][1,4]benzodiazepin-3(R)-yl]pyridine-4-carboxamide,3-[3-(Cyclopentyloxy)-4-methoxybenzyl]-6-(ethylamino)-8-isopropyl-3H-purinehydrochloride,4-[6,7-Diethoxy-2,3-bis(hydroxymethyl)naphthalen-1-yl]-1-(2-methoxyethyl)pyridin-2(1H)-one,2-carbomethoxy-4-cyano-4-(3-cyclopropylmethoxy-4-difluroromethoxyphenyl)cyclohexan1-one,cis[4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-1-ol,ONO-6126 (Eur Respir J 2003, 22(Suppl. 45): Abst 2557) and the compoundsclaimed in the PCT patent applications number WO03/097613 andPCT/EP03/14722 and in the Spanish patent application number P200302613.

Examples of suitable corticosteroids and glucocorticoids that can becombined with β2-agonists are prednisolone, methylprednisolone,dexamethasone, naflocort, deflazacort, halopredone acetate, budesonide,beclomethasone dipropionate, hydrocortisone, triamcinolone acetonide,fluocinolone acetonide, fluocinonide, clocortolone pivalate,methylprednisolone aceponate, dexamethasone palmitoate, tipredane,hydrocortisone aceponate, prednicarbate, alclometasone dipropionate,halometasone, methylprednisolone suleptanate, mometasone furoate,rimexolone, prednisolone farnesylate, ciclesonide, deprodone propionate,fluticasone propionate, halobetasol propionate, loteprednol etabonate,betamethasone butyrate propionate, flunisolide, prednisone,dexamethasone sodium phosphate, triamcinolone, betamethasone17-valerate, betamethasone, betamethasone dipropionate, hydrocortisoneacetate, hydrocortisone sodium succinate, prednisolone sodium phosphateand hydrocortisone probutate.

Examples of suitable M3 antagonists (anticholinergics) that can becombined with β2-agonists are tiotropium salts, oxitropium salts,flutropium salts, ipratropium salts, glycopyrronium salts, trospiumsalts, revatropate, espatropate,3-[2-Hydroxy-2,2-bis(2-thienyl)acetoxy]-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octanesalts,1-(2-Phenylethyl)-3-(9H-xanthen-9-ylcarbonyloxy)-1-azoniabicyclo[2.2.2]octanesalts, 2-oxo-1,2,3,4-tetrahydroquinazoline-3-carboxylic acidendo-8-methyl-8-azabicyclo[3.2.1]oct-3-yl ester salts (DAU-5884),3-(4-Benzylpiperazin-1-yl)-1-cyclobutyl-1-hydroxy-1-phenylpropan-2-one(NPC-14695),N-[1-(6-Aminopyridin-2-ylmethyl)piperidin-4-yl]-2(R)-[3,3-difluoro-1(R)-cydopentyl]-2-hydroxy-2-phenylacetamide(J-104135),2(R)-Cyclopentyl-2-hydroxy-N-[1-[4(S)-methylhexyl]piperidin-4-yl]-2-phenylacetamide(J-106366),2(R)-Cyclopentyl-2-hydroxy-N-[1-(4-methyl-3-pentenyl)-4-piperidinyl]-2-phenylacetamide(J-104129),1-[4-(2-Aminoethyl)piperidin-1-yl]-2(R)-[3,3-difluorocyclopent-1(R)-yl]-2-hydroxy-2-phenylethan-1-one(Banyu-280634),N—[N-[2-[N-[1-(Cyclohexylmethyl)piperidin-3(R)-ylmethyl]carbamoyl]ethyl]carbamoylmethyl]-3,3,3-triphenylpropionamide(Banyu CPTP), 2(R)-Cyclopentyl-2-hydroxy-2-phenylacetic acid4-(3-azabicyclo[3.1.0]hex-3-yl)-2-butynyl ester (Ranbaxy 364057),UCB-101333, Merck's OrM3,7-endo-(2-hydroxy-2,2-diphenylacetoxy)-9,9-dimethyl-3-oxa-9-azoniatricyclo[3.3.1.0(2.4)]nonanesalts,7-(2,2-diphenylpropionyloxy)-7,9,9-trimethyl-3-oxa-9-azoniatricyclo[3.3.1.0*2,4*]nonanesalts,7-hydroxy-7,9,9-trimethyl-3-oxa-9-azoniatricyclo[3.3.1.0*2,4*]nonane9-methyl-9H-fluorene-9-carboxylic acid ester salts, all of themoptionally in the form of their racemates, their enantiomers, theirdiastereomers and mixtures thereof, and optionally in the form of theirpharmacologically-compatible acid addition salts. Among the saltschlorides, bromides, iodides and methanesuiphonates are preferred.

The combinations of the invention may be used in the treatment ofrespiratory diseases, wherein the use of bronchodilating agents isexpected to have a beneficial effect, for example asthma, acute orchronic bronchitis, emphysema, or Chronic Obstructive Pulmonary Disease(COPD).

The active compounds in the combination, i.e. the β2-agonist of theinvention and the PDE4 inhibitors, corticosteroids or glucocorticoidsand/or anticholinergics may be administered together in the samepharmaceutical composition or in different compositions intended forseparate, simultaneous, concomitant or sequential administration by thesame or a different route.

It is contemplated that all active agents would be administered at thesame time, or very close in time. Alternatively, one or two activescould be taken in the morning and the other(s) later in the day. Or inanother scenario, one or two actives could be taken twice daily and theother(s) once daily, either at the same time as one of the twice-a-daydosing occurred, or separately. Preferably at least two, and morepreferably all, of the actives would be taken together at the same time.Preferably, at least two, and more preferably all actives would beadministered as an admixture.

The active substance compositions according to the invention arepreferably administered in the form of compositions for inhalationdelivered with the help of inhalers, especially dry powder inhalers,however, any other form or parenteral or oral application is possible.Here, the application of inhaled compositions embodies the preferredapplication form, especially in the therapy of obstructive lung diseasesor for the treatment of asthma.

Additional suitable carriers for formulations of the active compounds ofthe present invention can be found in Remington: The Science andPractice of Pharmacy, 20th Edition, Lippincott Williams & Wilkins,Philadelphia, Pa., 2000. The following non-limiting examples illustraterepresentative pharmaceutical compositions of the invention.

Formulation Example 1 Oral Suspension

Ingredient Amount Active Compound 3 mg Citric acid 0.5 g Sodium chloride2.0 g Methyl paraben 0.1 g Granulated sugar 25 g Sorbitol (70% solution)11 g Veegum K 1.0 g Flavoring 0.02 g Dye 0.5 mg Distilled water q.s. to100 ml

Formulation Example 2 Hard Gelatine Capsule for Oral Administration

Ingredient Amount Active Compound 1 mg Lactose 150 mg Magnesium stearate3 mg

Formulation Example 3 Gelatin Cartridge for Inhalation

Ingredient Amount Active Compound (micronized) 0.2 mg Lactose 25 mg

Formulation Example 4 Formulation for Inhalation with a DPI

Ingredient Amount Active Compound (micronized) 15 mg Lactose 3000 mg

Formulation Example 5 Formulation for a MDI

Ingredient Amount Active Compound (micronized) 10 g1,1,1,2,3,3,3-heptafluoro-n-propane q.s. to 200 ml

Biological Assays

The compounds of this invention, and their pharmaceutically-acceptablesalts, exhibit biological activity and are useful for medical treatment.The ability of a compound to bind to the β adrenergic receptors, as wellas its selectivity, agonist potency, and intrinsic activity can bedemonstrated using Tests A to E below, or can be demonstrated usingother tests that are known in the art.

Test A

Human Adrenergic β1 and β2 Receptor Birding Assays

The study of binding to human adrenergic β1 and β2 receptors wasperformed using commercial membranes prepared from Sf9 cells where theyare overexpressed (Perkin Elmer).

The membrane suspensions (16 μg/well for β1 and 5 μg/well for β2) inassay buffer, 75 mM Tris/HCl with 12.5 mM MgCl₂ and 2 mM EDTA pH=7.4,were incubated with 0.14 nM ³H-CGP12177 (Amersham) and differentconcentrations of the test compounds, in a final volume of 250 μl, inGFC Multiscreen 96 well plates (Millipore) pretreated with +0.3% PEI.Non specific binding was measured in the presence of 1 μM propanolol.Incubation was for 60 minutes at room temperature and with gentleshaking. The binding reactions were terminated by filtration and washingwith 2.5 volumes of Tris/HCl 50 mM pH=7.4. The affinity of each testcompound to the receptor was determined by using at least six differentconcentrations ran in duplicate. IC₅₀ values were obtained by non-linearregression using SAS.

Exemplified compounds of this invention were found to have IC₅₀ valuesless than 25 nM for β2 receptor and more than 140 nM for β1 receptor

Test B

Human Adrenergic β3 Receptor Binding Assay

Membranes prepared from Human SK-N-MC neurotumor cells from the AmericanType Culture Collection were used as the source of β3 receptor. Thecells were grown, and the membranes prepared following the methodsdescribed in P. K. Curran and P. H. Fishman, Cell. Signal, 1996, 8 (5),355-364.

The assay procedure as detailed in the mentioned publication can besummarized as follows: the SK-N-MC cell line expresses both β1 and β3receptor and for that reason, for selective binding to β3, membraneswere incubated with 1 nM ¹²⁵I-CYP ((−)-3-[¹²⁵I]Iodocyanopindolol(Amersham)) and 0.3 μM CGP20712A (a β1 antagonist) in 50 mM HEPES, 4 mMMgCl₂ and 0.4% bovine serum albumin, pH=7.5 (assay buffer), anddifferent concentrations of the test compounds. The final volume of theassay was 250 μl. Non specific binding was defined by 100 μM alprenolol.The samples were incubated 90 minutes at 30° C. with shaking.

The binding reactions were terminated by filtration through Whatman GF/Cmembranes, prewet in assay buffer at 4° C., using a BRANDEL M-24harvester. The filters were washed three times with 4 ml each of 50 mMTris/HCl and 4 mM MgCl₂ pH 7.4, and the radioactivity, retained in thefilters, measured.

The affinity of each test compound to the receptor was determined byusing at least eight different concentrations ran in duplicate. IC₅₀values were obtained by non-linear regression using SAS. Exemplifiedcompounds of this invention were found to have IC₅₀ values more than1200 nM for β3 receptor.

Test C

Determination of Agonist Activity, Onset and Offset onElectrically-Stimulated Guinea-Pig Trachea

Preparation of Isolated Trachea Strip

Adult, male guinea pigs (400-500 g) were killed by a blow to the headwith subsequent exsanguinations, and tracheas were excised and placed inKrebs solution in a Petri dish. The adherent connective tissue wasdissected away and the lumen gently flushed with Krebs solution. Eachtrachea was dissected into rings containing 3-4 cartilage bands and therings opened to form strips by cutting through the cartilage on the sideopposite to the smooth muscle band. A long, cotton thread was attachedto the cartilage at one end of the strip for attachment to the straingauge, and a cotton loop to the other end for anchoring the tissue inthe superfusion chamber containing 2.8 μM indomethacin. Bipolar platinumelectrodes were positioned in parallel with and in close proximity tothe superfused tissue. Tissues were then left for one hour to stabilize.

Electrical-Stimulation

Electrical stimulation (Coleman & Niels, 1989) was delivered as squarewave pulses of 10-second trains every 2 minutes at a frequency of 5 Hzand a duration of 0.1 ms. In each experiment, the voltage was chosenfollowing construction of a voltage-dependent response curve from 8-16 Vand selecting a supramaximal dose within 10-15% of the maximum response.To establish a baseline, trachea strips were stimulated for a minimum of20 minutes (10 peaks) at this supramaximal voltage.

Tissue Superfusion

The superfusion apparatus employed in these experiments has beendescribed previously (Coleman & Niels, 1989). Preparations were mountedunder a resting tension of 1 g. For the entire duration of theexperiment trachea strips were superfused at a rate of 2 ml min⁻¹ withoxygenated (5% CO₂ in O₂) Krebs Henseleit solution at 37° C.

Drug Preparation

Stock drug solutions were prepared by dissolving the compounds in water.Stock solutions were then diluted in Krebs Henseleit solution to preparedifferent concentration ranges per each compound.

Determination of Agonist Activity

Agonist activity was determined by sequentially infusing increasingconcentrations of drug prepared in the Krebs solution during 30 minutes.The magnitude of each response was measured and expressed as apercentage of inhibition over the electrically-induced contractileresponse. Potency values for the β-adrenoceptor agonists were expressedin absolute terms (concentration required to induce a 50% inhibition,EC₅₀).

Determination of Onset of Action

The time to reach a 50% onset of action (T₅₀ onset) is defined as thetime spanning from drug agonist administration to 50% attainment themaximum response at an EC₅₀ drug concentration.

The time to reach maximum onset of action (T_(max)) is defined as thetime spanning from drug agonist administration to attainment of a 100%of the maximum response at an EC₅₀ concentration of drug.

Determination of Offset of Action

The time to 50% offset of action is defined as the time elapsed from theend of drug administration to attainment of 50% relaxation recovery.

In the same experiment, offset of action was also expressed as thepercentage of recovery reached 8 h after drug administration.

Exemplified compounds of this invention that were tested in this assayshow EC₅₀ values less than 10 nM with more than 500 minutes as time to50% recovery.

Test D

Histamine-Induced Bronchospasm in Conscious Guinea Pigs

Test Compounds and Products

The test compounds were dissolved in distilled water. Some of them needto be dissolved using 10% polyethylene glycol 300. Histamine HCl wassupplied by Sigma (code H 7250) and dissolved in distilled water.

Experimental Procedure

Male guinea-pigs (325-450 g) were supplied by Harlan (Netherlands), andmaintained at a constant temperature of 22±2° C., humidity 40-70% with10 cycles of room air per hour. They were illuminated with artificiallight in 12 hour cycles (from 7 h am to 7 h pm), A minimum of 5 daysacclimatization period was left before animals were dosed with testcompounds. The animals were fasted for 18 hours before the experimentwith water ad libitum.

Five animals per session were placed in a methacrylate box (47×27×27 cm)which was connected to an ultrasonic nebuliser (Devilbiss Ultraneb 2000,Somerset, Pa., USA). The test compounds (β2-adrenergic agonists) wereadministered by aerosol during 30 seconds at concentrations between 0.1and 1000 μg/ml. Either 5 or 180 min after test compounds administration,250 μg/ml of histamine were nebulized during 30 s to induce abronchospasm. The animals were observed during 5 minutes after histamineadministration and the time elapsed from administration to firstbronchospasm was recorded.

Determination of Activity, Duration of Action and Calculations

For each treatment and dosage the percentage of delay of bronchospasmwas calculated using the following formula: % delaybronchospasm=[(t′−t)/(t_(max)−t)]×100, where t_(max)=maximum observationtime (5 min), t=time elapsed to first bronchospasm in the animals ofcontrol group, and t′=time elapsed to first bronchospasm incompound-treated animals. The EC₅₀ was defined as the concentration dosecausing a 50% delay of bronchospasm. An EC₅₀ was calculated forcompounds administered 5 minutes or 180 min before histamine challengeand were named EC₅₀ at 5 min and EC₅₀ at 180 min, respectively.

Duration of action of test compounds was determined by the ratio EC₅₀ 5min/EC₅₀ 180 min. The compounds exhibiting a ratio EC₅₀ 5 min/EC₅₀ 180min below 100 were considered long-acting.

Exemplified compounds of this invention show long duration of action.

Test E

Acetylcholine-Induced Bronchoconstriction in Guinea Pig

Test Compounds and Products

The test compounds were dissolved in distilled water. Some of them needto be dissolved using a maximum of 10% polyethylene glycol 300.Acetylcholine HCl was supplied by Sigma (code A 6625) and dissolved insaline solution.

Experimental Procedure

Male guinea-pigs (450-600 g) were supplied by Harlan (Netherlands), andmaintained at a constant temperature of 22±2° C., humidity 40-70% with10 cycles of room air per hour. They were illuminated with artificiallight in 12 hour cycles (from 7 h am to 7 h pm). A minimum of 5 daysacclimatization period was left before animals were dosed with testcompounds. The animals were fasted 18 hours before the experiment withwater ad libitum.

Guinea pigs were exposed to an aerosol of a test compound or vehicle.These aerosols were generated from aqueous solutions using a Devilbissnebuliser (Model Ultraneb 2000, Somerset, Pa., SA). A mixture of gases(CO₂=5%, O₂=21%, N₂=74%) was flown through the nebuliser at 3 L/minute.This nebuliser was connected to a methacrylate box (17×17×25 cm) wherethe animals were placed one per session. Every guinea pig remained inthe box for a total of 10 minutes. Aerosols were generated at 0 and 5minutes during 60 seconds each one (approximately 5 mL of solution wasnebulised).

Aerosol concentrations between 0.1 and 300 μg/ml of the compounds wereadministered. The bronchoprotective effects of test compounds wereevaluated one hour or twenty four hours post-dose with a Mumed PR 800system.

Determination of Bronchoprotective Effect and Calculations

The guinea pigs were anesthetized with an intramuscular injection ofketamine (43.75 mg/kg), xylazine (83.5 mg/kg), and acepromazine (1.05mg/kg) at a volume of 1 ml/kg. After the surgical site was shaved, a 2-3cm midline incision of the neck was made. The jugular vein was isolatedand cannulated with a polyethylene catheter (Portex Ld.) to allow anintravenous bolus of acetylcoline (10 and 30 μg/kg iv) at 4-minintervals. The carotid artery was cannulated and the blood pressure wasmeasured by a Bentley Tracer transducer. The trachea was dissected andcannulated with a teflon tube and connected at a pneumotachographFleisch for measuring the airflow. Animal was ventilated using an UgoBasile pump, with a volume of 10 ml/kg at a rate of 60 breaths/min. Thetranspulmonary pressure was measured with an esophageal cannula(Venocath-14, Venisystems) connected to Celesco transducer. Once thecannulations were completed a Mumed pulmonary measurement computerprogram enabled the collection of pulmonary values. The baseline valueswere within the range of 0.3-0.9 mL/cm H₂O for compliance and within therange of 0.1-0.199 cm H₂O/mL per second for lung resistance (R_(L)).

The bronchocoprotective effect of inhaled compounds was determined withthe concentration of the test compound causing a 50% of inhibition ofbronchoconstriction (EC₅₀) induced by acetylcholine at 30 μg/kg iv

Determination of Duration of Action

Exemplified compounds of this invention show long duration of action.

1. A compound of formula (I):

wherein: R¹ is chosen from —CH₂OH and —NHC(O)H; R² is a hydrogen atom;R³ is chosen from a hydrogen atom, halogen atoms, —SO—R⁵, —SO₂—R⁵,—NH—CO—NH₂, CO—NH₂, C₁₋₄alkyl, C₁₋₄alkoxy and —SO₂NR⁵R⁶; R⁴ is chosenfrom a hydrogen atom, halogen atoms, and C₁₋₄ alkyl groups; R⁵ is chosenfrom C₁₋₄ alkyl groups and C₃₋₈ cycloalkyl groups; R⁶ is independentlychosen from a hydrogen atom and C₁₋₄ alkyl groups; n, p and q are eachindependently 0, 1, 2, 3 or 4; m and s are each independently 0, 1, 2 or3; and r is 0, 1 or 2 with the provisos that: at least one of m and r isnot 0 the sum n+m+p+q+r+s is 7, 8, 9, 10, 11, 12 or 13 the sum q+r+s is2, 3, 4, 5 or 6 or a pharmaceutically-acceptable salt or stereoisomerthereof.
 2. The compound according to claim 1, wherein at least one of mand r is
 1. 3. The compound according to claim 2, wherein the sum m+ris
 1. 4. The compound according to claim 1, wherein the sum n+m+p+q+r+sis 8, 9 or
 10. 5. The compound according to claim 1, wherein the sumq+r+s is 2, 3 or
 4. 6. The compound according to claim 1, wherein s isan integer chosen from 0 and
 1. 7. The compound according to claim 1,wherein the sum n+p is 4, 5 or
 6. 8. The compound according to claim 1,wherein the sum q+s is 1, 2, 3 or
 4. 9. The compound according to claim1, wherein R³ is chosen from a hydrogen atom, halogen atoms, and amethyl group.
 10. The compound according to claim 9, wherein R³ is achlorine or fluorine atom.
 11. The compound according to claim 9,wherein R³ is a methyl group.
 12. The compound according to claim 1,wherein R⁴ is a hydrogen atom.
 13. The compound according to claim 1,wherein R⁴ is a chlorine atom.
 14. The compound according to claim 1,wherein m and s are each 0, r and q are each 1, the sum of n and p is 6and R⁵ and R⁶ are both hydrogen atoms.
 15. A compound according to claim1, chosen from:(R,S)-4-(2-{[6-(2,2-Difluoro-4-phenylbutoxy)hexyl]amino}-1-hydroxy-ethyl)-2-(hydroxymethyl)phenol,(R,S)-4-(2-{[6-(2,2-Difluoro-2-phenylethoxy)hexyl]amino}-1-hydroxy-ethyl)-2-(hydroxymethyl)phenol,(R,S)-4-(2-{[4,4-Difluoro-6-(4-phenylbutoxy)hexyl]amino}-1-hydroxy-ethyl)-2-(hydroxymethyl)phenol,(R,S)-4-(2-{[6-(4,4-Difluoro-4-phenylbutoxy)hexyl]amino}-1-hydroxy-ethyl)-2-(hydroxymethyl)phenol,(R,S)-4-[2-({6-[2,2-Difluoro-2-(3-methylphenyl)ethoxy]hexyl}amino)-1-hydroxyethyl]-2-(hydroxymethyl)phenol,4-[(1R)-2-{[6-(2,2-Difluoro-2-phenylethoxy)hexyl]amino}-1-hydroxyethyl)-2-(hydroxymethyl)phenol,(R,S)-2-(Hydroxymethyl)-4-(1-hydroxy-2-{[4,4,5,5-tetrafluoro-6-(3-phenylpropoxy)hexyl]amino}ethyl)phenol,(R,S)-[5-(2-{[6-(2,2-Difluoro-2-phenylethoxy)hexyl]amino}-1-hydroxy-ethyl)-2-hydroxyphenyl]formamide,(R,S)-4-[2-({6-[2-(3-Bromophenyl)-2,2-difluoroethoxy]hexyl}amino)-1-hydroxyethyl]-2-(hydroxymethyl)phenol,(R,S)—N-[3-(1,1-Difluoro-2-{[6-({2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}ethyl)phenyl]urea,(R,S)-4-[2-({6([2,2-difluoro-2-(3-methoxyphenyl)ethoxy]hexyl}amino)-1-hydroxyethyl]-2-(hydroxymethyl)phenol,4-((1R)-2-{[4,4-Difluoro-6-(4-phenylbutoxy)hexyl]amino}-1-hydroxy-ethyl)-2-(hydroxymethyl)phenol,(R,S)-4-(2-{[6-(3,3-Difluoro-3-phenylpropoxy)hexyl]amino}-1-hydroxyethyl)-2-(hydroxymethyl)phenol,(R)-4-(2-{[6-(2,2-Difluoro-2-phenylethoxy)-4,4-difluorohexyl]amino}-1-hydroxyethyl)-2-(hydroxymethyl)phenol,(R,S)-4-(2-{[6-(2,2-difluoro-3-phenylpropoxy)hexyl]amino}-1-hydroxyethyl)-2-(hydroxymethyl)phenol, hydrochloride, or apharmaceutically-acceptable salt thereof.
 16. A pharmaceuticalcomposition comprising a therapeutically effective amount of a compoundaccording to claim 1, and a pharmaceutically acceptable carrier.
 17. Thepharmaceutical composition according to claim 16, wherein thecomposition further comprises a therapeutically effective amount of atleast one therapeutic agent.
 18. The pharmaceutical compositionaccording to claim 17, wherein the at least one therapeutic agent ischosen from corticosteroids, antichlolinergic agents, and PDE4inhibitors.
 19. The pharmaceutical composition according to claim 16,formulated for administration by inhalation.